Title: Key requirements for successful transnational drug discovery projects
Fraunhofer Institute for Molecular Biology & Applied Ecology – ScreeningPort, Germany
Title: Key requirements for successful transnational drug discovery projects
Fraunhofer Institute for Molecular Biology & Applied Ecology – ScreeningPort, Germany
Dr Sheraz Gul is Head of Drug Discovery, Assay Development & Screening at the Fraunhofer Institute for Molecular Biology and Applied Ecology. He is responsible for the global management of drug discovery activities and has 23 years’ experience in both academia (University of London) and industry (GlaxoSmithKline Pharmaceuticals). This has ranged from the detailed study of catalysis by biological catalysts (enzymes and catalytic antibodies) to the design and development of assays for High Throughput Screening for the major drug target classes. He is the co-author of numerous papers, chapters and the Enzyme Assays: Essential Data handbook and has been organising drug discovery since 2011 across the world (Brazil, Hamburg, Italy, Portugal, Saudi Arabia and U.S.A) and thus far has been involved in the training of over 350 scientists. In addition, he has been appointed to the editorial boards of the European Pharmaceutical Review and International Drug Discovery, is the Scientific Editor of Drug Target Review, a scientific co-founder of Transcriptogen Ltd and is an advisor to a number of biotech companies.
We are now witnessing a resurgence in drug discovery the use of cell-based assays including phenotypic assays where the underlying target/s are unknown. Concomitantly, significant advances in these assays are also being made, for example using human induced pluripotent stem (iPS) cell-derived cells that better recapitulate normal human biology compared to transformed cell lines and non-human primary cells. A typical small molecule drug discovery project aims to identify chemical starting points that modify the functions of genes, cells, or biochemical pathways ultimately leading to new therapeutics. Screening using miniaturised microtiter plate formats remains the most widely utilised methodology for identifying novel chemical starting points that are capable of modulating target function in a meaningful, biologically relevant manner. The initial steps in small molecule drug discovery include the selection of a target, development of an assay to monitor its activity, and its screening against a compound library. Subsequently, the Primary Hits are optimised using multiple criteria including structure activity relationships,selectivity, physicochemical properties and liability that could result in a Lead compound series and eventually a clinical Candidate molecule for evaluation in human subjects and this compound is expected to possess appropriate physico-chemical properties, in-vitro off target liabilities, in-vitro toxicity and in-vitro ADME and safety profiles in order to improve their probability of progressing in the drug discovery value chain. This presentation will discuss the strategies that have been adopted by various translational drug discovery projects with a specific focus on small molecule therapeutics.
Title: Applications in pharmaceuticals and drug analysis of modified carbon paste electrodes using different voltammetric techniques
South Valley University, Egypt
Mahmoud Khodari Maeila Hamed is a Prof. of Analytical chemistry in South Valley University, Qena, Egypt. His education is B.SC. (general chemistry) at May 1980 Assiut University, Egypt, M.Sc. (Analytical chemistry) 1985, Assiut University and Ph.D at (Analytical Chemistry) 1990, ULB, Belgium- Assiut University, Egypt. His Publications are 54 in the field of analytical chemistry, drug analysis. He attended 21 conferences and meetings.
Carbon paste electrodes (CPEs) which consists of a mixture carbon( graphite) with organic liquid, was used as a working electrode for selective and sensitive determination of some pharmaceuticals and drugs. To enhance the sensitivity, the carbon paste electrode was modified using different additives such as fatty acids, nanostructure materials, and others were added to the paste. This specific area of applied analytical chemistry offers extraordinary wide employment of CPEs and MCPEs in pharmaceutical analysis. On using Voltammetric procedures, different compounds accumulated and adsorbed on the electrode surface and reduced or oxidized giving a peak current corresponds the concentration of investigated analyte. The methods were applied to determine the drugs or pharmaceuticals in biological media or in pharmaceutical formulation, a detection limit of about 1 x 10 -10M was achieved in some cases.
Title: Ruthenium-conjugated synthetic flavonoid derivatives as novel modulators of platelet function
University of Reading, Reading, UK
Dr. Sakthivel Vaiyapuri is a Lecturer in Pharmacology in the School of Pharmacy at the University of Reading, UK. I completed my Bachelors in Biochemistry at Bharathidasan University and Masters in Biotechnology at the University of Madras, India. Ireceived my PhD in the field of snake venoms and postdoctoral experience in cardiovascular diseases with specific interest on platelet signalling from the University of Reading. Currently, my research group involved in the functional characterisation of inflammatory molecules such as formyl peptide and toll-like receptors in the modulation of platelet function at the interface between thrombosis and inflammation. With the better understanding of these receptors, we develop target-specific chemical molecules in collaboration with colleagues in Pharmaceutical chemistry and evaluate their biological effects in the modulation of thromboinflammatory responses. Furthermore, we are also engaged in analysing the toxic components of snake venoms and their impact on various functions of cardiovascular system.
Background: Platelets (small circulating blood cells) play indispensable roles in the regulation of haemostasis via blood clotting. However, their inappropriate activation leads to thrombosis, which obstructs blood flow to major organs such as heart and brain resulting in heart attack and stroke respectively. Hence, platelets act as a promising target to treat/prevent cardiovascular diseases (primarily thrombotic diseases). Direct relationships between cardiovascular health and dietary flavonoids have been extensively studied for a long period. Nevertheless, numerous challenges are associated with the use of dietary components in biological systems for the prevention and treatment of diseases. Some of these include the poor absorption in intestine, the reduced bioavailability in blood stream, inability to readily cross the cell membranes and their modest stability in biological systems. Here, we report the design, synthesis, chemical characterisation and biological evaluation of Ruthenium complexes of chrysin(a natural flavonoid), and its synthesised thioflavone derivative for the modulation of platelet function and thrombus formation. Methods and Results: In this study, we analysed the effects of chrysin in the modulation of platelet reactivity using washed human platelets and platelet-rich plasma by optical aggregometry. Similar to other flavonoids, chrysin displayed substantially reduced effectswhen platelet-rich plasma was used in comparison to washed platelets. In order to intensify the effects of chrysin under physiological conditions such as in whole blood, its sulphur (thio-chrysin) and Ruthenium (Ru-chrysin and Ru-thio-chrysin) conjugated synthetic derivatives were synthesised and characterised. The effects of synthetic chrysin derivatives were examined in platelets using a variety ofplatelet functional assays such as aggregation, the measurement of fibrinogen binding and P-selectin levels, calcium mobilisation and in vitro thrombus formation. In comparison to natural chrysin, Ruthenium- conjugated chrysin derivatives, specifically Ru-thio-chrysin significantly reduced distinctive functions of plateletsand thrombus formation under arterial flow conditions at minimum of 6.25μM. Together, these results demonstrate that Ruthenium- based synthetic chrysin derivatives exert enhanced inhibitory effects in platelets under physiological conditions. Conclusions: This study highlights the importance of Ruthenium-conjugated synthetic flavonoid derivatives in the modulation of platelet function and thrombus formation. Due to their numerous beneficial effects in biological systems, Ruthenium-conjugated molecules will be greatlyvaluable in therapeutical applications for the prevention and treatment of cardiovascular (particularly thrombotic) diseases.
Title: Lead modification approaches in the design, synthesis and evaluation of novel chemical entities for muscarinic acetylcholine receptors
Richie R. Bhandare
Ajman University of Science and Technology, UAE
Richie R. Bhandare received his B.Pharm and M.Pharm from University of Mumbai and PhD in Medicinal Chemistry from School of Pharmacy, Temple University, Philadelphia, USA in 2013. He was working at a leading Pharmacy College in Mumbai as an Assistant Professor in Pharmaceutical Chemistry. He has guided 13 M.Pharm students. He works in the area of designing novel compounds for muscarinic, serotonergic and retinoic receptors and organic reaction method development. He will now be associated with College of Pharmacy and Health Sciences, Ajman University of Science and Technology, Ajman, UAE as an Assistant Professor in Medicinal Chemistry.
Purpose: The goal of this study was to modify structurally our low affinity lead lactones in an effort to improve receptor affinity. The design of new chemical entities for muscarinic receptors was based on molecular modeling and structure activity relationship studies from the literature and our previous work. Methods: Lead Lactone-containing compounds previously synthesized in our laboratory demonstrated moderate affinity for muscarinic receptors. Structure activity relationship (SAR) data from the literature suggest that specific amine-containing functionalities repeatedly appear in high affinity muscarinic ligands. Based on these reports, various lead modification approaches were utilized in order to design a series of novel muscarinic ligands containing the lactone ring (or bioisostere) and an amine-containing fragment reported in other high affinity ligands. Homologation approach was selected in the design of a series of lactone based compounds. Bioisosteric approach for the lactone ring replacement (e.g., substituted tetrahydrofuran, 1,3-benzodioxoles, oxazolidinones and chromone) were also investigated. The need for rapid and efficient routes to the scaffolds prompted the development of several highly efficient synthetic methods to structurally diverse target compounds. Test compounds were evaluated for affinity in muscarinic binding assays. The ligands exhibiting % specific inhibition >50% were selected for further evaluation (IC50 data and ultimately subtype selectivity). Results: A lactone-based ligand having diphenylmethylpiperazine fragment was identified as non-selective muscarinic ligand with IC50 of 340 nM whereas its homolog was found to have higher affinity (IC50 of 17 nM). Preliminary binding study suggests that substituted tetrahydrofuran, 1,3-benzodioxoles, oxazolidinones and chromone nuclei represent possible bioisosteric replacements for the lactone ring in the series of ligands evaluated herein. The ligands evaluated for subtype selectivity in the muscarinic assays were found to be non-selective. Conclusions: Novel synthetic routes were developed for the synthesis of target compounds. The compounds reported herein represent an interesting series of novel muscarinic ligands that require further study. The design of future ligands will be based on the SAR data supplied in this work as well as SAR studies reported in the literature.
Title: Biological activity of nanocomposites consisting of TiO2 nanoparticles and antisense oligonucleotides
Novosibirsk State University, Russia
Asya S. Levina was born in Novosibirsk, Russia. She received the MS degree in chemistry from Novosibirsk State University, Russia, in 1969 and the Ph.D. degree in bioorganic chemistry from Novosibirsk Institute of Organic Chemistry in 1974.From 1969 to 1993, she worked in the Laboratory of Nucleic Acids Chemistry at the Institute of Bioorganic Chemistry. From 1993 to 1997, she was Senior Research Associate with the Laboratory in Worcester Foundation for Biomedical Research, Shrewsbury, MA, USA. Since 1997, she has been a Senior Research Scientist at the Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences. She is the author of more than 100 articles and more than 10 patents. Her research interests include the synthesis of oligonucleotides and their derivatives, preparation of DNA arrays, and the synthesis of nucleic acid-based nanocomposites. Currently she works at the Novosibirsk State University.
Nanocomposites consisting of titanium dioxide nanoparticles (TiO2)and oligonucleotides or their analogs were prepared to deliver nucleic acid-based compounds into cells. The nanocomposites (TiO2•PL-oligo)were designed by the immobilization of polylysine-containing oligonucleotidesonTiO2 nanoparticles. It was shown that the proposed nanocomposites exhibited a low toxicity and very high activity against influenza A virus (IAV) in vitro and in vivo. The nanocomposites bearing the oligonucleotide targeted to the chosen regions of (-)RNA and (+)RNA of segment 5 of different IAV subtypes inhibited the virus reproduction by >99%. Moreover, it was shown a possibility of using the proposed nanocomposites for the treatment of hypertensive disease by introducing them into the hypertensive ISIAH ratsdeveloped as a model of the stress-sensitive arterial hypertension. Oligonucleotides should be targeted to some genes involved in the pathogenesis of essential hypertension. The angiotensin-converting enzyme (ACE) involved in the synthesis of angiotensin-II was chosen as a target. Two ways of administration (intraperitoneal injection and inhalation) were examined. Both methods showed a significant (by 20-30 mm/Hg) decrease in systolic blood pressure, when the nanocomposite contained the ACE gene-targeted oligonucleotide. When using the oligonucleotide with a random sequence, no effect was observed. Thus, it was demonstrated a possibility of using the proposed nanocomposites as efficient drugs to achieve a high biological efficacy. “The work was supported by the grant of Russian Scientific Foundation no. 16-15-10073.”
Title: Bisphenol an analogues bind to ras proteins and compete with guanine nucleotide exchange
Ruhr University of Bochum, Germany
Raphael Stoll is Professor of Biomolecular Spectroscopy in the Faculty of Chemistry and Biochemistry at the Ruhr University of Bochum, Germany. He studied Physiological Chemistry and Biochemistry at the Universities of Tübingen, Germany, and Oxford, UK, as a fellow of the „Studienstiftung” and DAAD. Supported by a fellowship from the FCI, he carried out his doctoral research at the Max Planck Institute for Biochemistry in Munich and received his PhD from the Technical University of Munich. After a stay as a research associate at The Scripps Research Institute, CA, USA funded by first a DAAD- and then an Emmy-Noether fellowship, he initially joined the Ruhr-University of Bochum as Juniorprofessor. His research focuses in the main on structure-function-relationships of medically-relevant proteins, specifically those involved in the development of cancerous tumours, in order to better understand the causes of the condition and propose more effective treatment strategies.
Bisphenols (BPs) are abundant in modern life, since they are widely used in numerous plastic products as plasticising agents. Humans are mainly exposed through canned foods to bisphenols, leading to the occurrence of BPs in human blood serum, urine, and sweat. Chemically, this family of compounds is characterised by an optionally substituted central sp3 carbon atom that is flanked by two hydroxyphenylfunctionalities. The protein K-Ras belongs to the family of small GTPases, which are enzymes that hydrolyse guanosine triphosphate (GTP) to guanosine diphosphate (GDP). Through switching between an active (GTP-loaded) and an inactive (GDP-loaded) state K-Ras acts as a molecular switch within cells. Furthermore, K-Ras is a known protein oncogene, because it is found to carry mutations in approx. 20 % of human cancers. Both, the activation states of K-Ras and the binding of small molecules to this GTPase can be investigated by nuclear magnetic resonance (NMR) spectroscopy. In addition, 1H-15N two-dimensional NMR spectra not only provide an opportunity to map the binding site of a ligand but also allow for the determination of the dissociation constant of a complex, a valuable parameter that helps to evaluate the impact of a ligand on a protein. In this work we show, based on our previous studies, that not only BPA but also analogues bind to K-Ras and we also discuss potential consequences of these interactions.
Title: Toward the design of novel antimicrobials: Synthesis and biological evaluation of phosphate isosters of fosmidomycin and analogs
Laboratoire Chimie et Biochimie de Molécules Bioactives – Université de Strasbourg/CNRS, France
Dr. Catherine Grosdemange-Billiard is Professor in Chemistry at “Université de Strasbourg”, France. Her scientific background is in fields as varied as biochemistry, organic synthesis, surface chemistry, bioorganic chemistry and medicinal chemistry. After a B Sc. in Biochemistry, a M Sc. in Chemistry, a PhDin Physical Chemistry, she joined the Georges Whitesides’ group at Harvard University as a postdoctoral fellow. Back to France, she was appointed to assistant professor. In 1995, she moved to Michel Rohmer’s group where she conducted research in chemistry and biochemistry of bacterial hopanoids. Since January 2014, she is the leader of the laboratory of “Chemistry and Biochemistry of Bioactive Molecules”. Her research interests are focused on the design of new antimicrobials.
Today, almost all important microbial infections throughout the world, such as tuberculosis, malaria, nosocomial diseases, are becoming resistant to antibiotics. Antimicrobial multi-drug resistance has been called one of the world's most pressing public health problems. It is therefore urgent to find innovative targets for new antimicrobial drugs. Proteins involved in isoprenoid biosynthesis represent such targets. Isoprenoids are found in all living organisms and are essential for all bacteria. The alternative mevalonate-independent methylerythritol phosphate (MEP) pathway for the biosynthesis of isoprenoids,which is present in many pathogenic bacteria e.g.Mycobacterium tuberculosis, M. leprae, as well as in opportunistic pathogens e.g. enterobacteria, Acinetobacter spp., Pseudomonas spp., and present in the parasitic Plasmodium species responsible for malaria but absent in human represents an attractive target for the design and development of new antimicrobials. We focus on developing novel inhibitors for 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), the second enzyme of the MEP pathway for isoprenoid biosynthesis in pathogens.
Title: Cardioprotective potential of a lanosteryltriterpene from Protorhuslongifolia
Rebamang A. Mosa
University of Zululand, Republic of South Africa
Dr. Rebamang Anthony Mosa has completed his PhD at the age of 35 years from University of Zululand. He is a senior lecturer at the University of Zululand and a registered member of the South African Council for Natural Scientific Professions (SACNASP). He has published over 15 papers in reputed journals. His area of expertise is in phytomedicine, currently focusing on bioactivities of plant-derived compounds against human metabolic disorders.
The current rapid increase in incidences of cardiovascular events indicates a need for discovery of new more effective cardioprotective agents. This study evaluated the cardioprotective effect of methyl-3β-hydroxylanosta-9, 24-dien-21-oate (RA-3) from Protorhuslongifolia stem bark. The cardioprotective effect of RA-3 was investigated in isoproterenol-induced myocardial injury in high fat diet (HFD)fed rats. Rats were randomly divided into the normal diet (ND) fed group and high fat diet (HFD) fed groups. The experimental hyperlipidemicgroup was orally administered with RA-3 (100 mg/kg body weight) for 15 days. The rats were then injected with isoproterenol (85mg/kg b.w) to induce myocardial injury. At the end of the experimental period,hearts and blood samples were collected and used for histology and biochemical assays, respectively. RA-3 exhibited cardioprotective effect as it minimized myocardial injury in HFD fed rats. Few lesions of acute hyaline degeneration and reduced fat deposition were observed in the heart tissue of the triterpene-treated rats. Lactate dehydrogenase activity waseffectively decreased in the blood of the triterpene-treated rats(44.1mU/mL) compared to the untreated group (64.8mU/mL). The RA-3 treatment also significantly decreased levels of serum total cholesterol (7.51 mmol/L) and LDL-c (4.46 mmol/L) with an increase in HDL-c (47.3 mmol/L) in HFD-induced hyperlipidemic rats relative to untreated control group. An increased glutathione content and catalase activity along with lower levels of malondialdehyde in the triterpene-treated animals (120.8 nmole/μL) than in the non-treated HFD fed rats (143.6 nmole/μL) were also observed. The results indicate that the triterpene has cardioprotective effect. It is apparent the triterpene has a potential to be used in the prevention and treatment of cardiovascular diseases and related health problems.
Title: Structural modifi cations of kidney cystatin in renal cancers
Mohd Anas Shamsi
Aligarh Muslim University, India
Title: Physicochemical analysis of antioxidant compounds in fresh juice from cactus cladodes
University Hassan 1er, Morocco
Title: Biomolecular NMR spectroscopy in medicinal chemistry
Ruhr University of Bochum, Germany
Raphael Stoll is Professor of Biomolecular Spectroscopy in the Faculty of Chemistry and Biochemistry at the Ruhr University of Bochum, Germany. He studied Physiological Chemistry and Biochemistry at the Universities of Tübingen, Germany, and Oxford, UK, as a fellow of the „Studienstiftung” and DAAD. Supported by a fellowship from the FCI, he carried out his doctoral research at the Max Planck Institute for Biochemistry in Munich and received his PhD from the Technical University of Munich. After a stay as a research associate at The Scripps Research Institute, CA, USA funded by first a DAAD- and then an Emmy-Noether fellowship, he initially joined the Ruhr-University of Bochum as Junior professor. His research focuses in the main on structure-function-relationships of medically-relevant proteins, specifically those involved in the development of cancerous tumours, in order to better understand the causes of the condition and propose more effective treatment strategies.
Biochemistry seeks to understand life at a molecular level by examining the relationship between the structure and function of biomolecules, such as proteins, nucleic acids, and lipids. To achieve this, we use a variety of techniques, particularly biomolecular NMR spectroscopy, in order to determine the three-dimensional structures and dynamics of biomolecules as well as how they interact with each other and other molecules in solution at near-physiological conditions. Cancer cells are hallmarked by the ability to divide unrestrictedly, posing an often lethal threat to an organism. Thus, the development of selective small antagonistic ligands tailored to bind to crucial protein targets is paramount to be able to treat cancer effectively. In order to achieve this goal, the molecular mechanism of a potential therapeutic effect needs to be elucidated at atomic resolution. Our research focuses in the main on medically-relevant proteins, specifically those involved in the development of cancerous tumours, in order to better understand the causes of the condition and propose more effective treatment strategies. Examples include oncogenic proteins, tumour suppressors as well as proteins involved in malignant melanoma, to name but a few. Other current areas of investigation also cover the structure, function, dynamics, and interaction of proteins associated with the transduction of physiological signals as well as bioenergetics. In particular, we would like to understand structure-function-relationships of MDM2, p53, Ras as well as Rheb GTPases, and the melanoma inhibitory activity (MIA) proteins. Our additional research efforts in medicinal chemistry include an “SAR by NMR”-like approach in order to develop potential lead structures of small molecular antagonists for these medically-relevant proteins. This presentation will cover recent advances from our research endeavours.
Title: Protective effects of apricot againist ketamin ıncuduced hepatotoxicity in rats
Inonu University, Turkey
I was born in Malatya province of Turkey in 1965. In 1987, I've finished University of Firat, Faculty of Veterinary Medicine, and finished Ph.D University of Selcuk, Health Sciences Institute in 2007. From February 2009, I've been working University of Inonu, Faculty of Pharmacy, Department of Pharmacology as Assistant Professor Dr.
ABSTRACT: The apricot is an important nutritional fruit in regard to it’s content of mineral and vitamins. It is well- known the benefical effects of the apricot on gastrointestinal, cardio-vascular, nervous and musculoskletal system. The aim of this study was to evaluate the hepato-protective effects of the dietary apricot in rats induced by ketamine toxicity in regard to biochemical, histopathological and immunohistochemical examinations. MATERIAL and METHODS: In this study; twenty eight, male, 12 week old, Sparaque Dawley rats were divided into 4 groups, 7 rats in each. Group I: control group. Group II: rats were injected intraperitoneally with ketamine (100 mg/kg/day) for two weeks. Group III: rats received 5% apricot containing diet for 15 days Group IV: rats received 5% apricot containing diet and intraperitoneally injected ketamine (100 mg/kg/day) for 15 days. Serum levels of AST, ALT, ALP, GGT, TB, ALB levels were measured. Histological Liver sections were subjected to H & E, immunohistochemical stain (Caspase 3) and followed by statistical analysis. In group II; liver enzymes and immunohistochemical caspase-3 positivity were significantly increased as compared to control. Furthermore, there was hepatocytic vacuoler degeneration, focal necrosis and sinusoidal hyperemia. These lesions were less severe in group IV, whereas caspase immunoreactivity were less significant in group IV. RESULTS: Overall, apricot containing diet has hepatoprotective effects on ketamine toxicity in rats.
Title: Fluoroquinolone-associated toxicities: Tipping the risk-benefit scale
Monique R. Bidell
Albany College of Pharmacy and Health Sciences, USA
Monique Bidell is currently an Assistant Professor of Pharmacy Practice at Albany College of Pharmacy and Health Sciences in Albany, NY. She maintains an active clinical practice site at St. Peter’s Hospital in Albany, NY. Dr. Bidell earned her Doctor of Pharmacy (PharmD) degreefrom Northeastern University in Boston, MA. She completed a year of postdoctoral residency training in Pharmacy Practice at Beth Israel Deaconess Medical Center in Boston, MA. She then completed a specialty residency in Infectious Diseases at the University of Chicago Medicine in Chicago, IL. She is a Board Certified Pharmacotherapy Specialist.
In the United States, fluoroquinolone antibiotics recently have gained increased attention due to safety concerns.In November 2015, a joint meeting of the Antimicrobial Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee was conducted to review risks and benefits of the systemic fluoroquinolone antibacterial drugs for the treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis in patients who have chronic obstructive pulmonary disease, and uncomplicated urinary tract infections.Potential fluoroquinolone-associated adverse events, both new and established, were a major focus of the Food and Drug Administration (FDA) advisory meeting discussion. Given emerging evidence that multiple toxicities can occur concurrently and result in potentially permanent disability, the condition “fluoroquinolone-associated disability,” or FQAD, was first described. In response to this advisory meeting, the FDA released a Drug Safety communication in May 2016 advising restricted use of fluoroquinolones for uncomplicated infections, as risks generally outweigh benefits. This presentation reviews established fluoroquinolone-associated adverse events, including tendinopathy, neurotoxicity, and arrhythmias, as well as emerging toxicities. Key findings from the FDA advisory meeting and FQAD data are also reviewed.
Title: Design, synthesis and biological characterization of chalcones and propanediones as inhibitors of histone methyl transferase against leukemia cell lines
C. S Ramaa
Bharati Vidyapeeth’s College of Pharmacy, India
Dr. Ramaa is professor, head of department of pharmaceutical chemistry at Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai. She received her Ph. D in pharmaceutical chemistry from Institute of chemical technology in 1997 and since then she has been associated with the BharatiVidyapeeth’s college. She has received several grants from renowned funding agencies like Lady Tata Memorial trust, Basic Research in Nuclear sciences. She has published more than twenty five research and review articles in international and national esteemed journals. She has also presented more than thirty presentations at national and international conferences. She has recently edited a special issue on drug reprofiling in Current topics in medicinal chemistry, Bentham sciences.
Cancer deaths rule the charts for over a decade with no persistent solution. Novel target specific therapy is an absolute need of the hour. Abundant work has been done and reported concerning the close liaison between inflammation and cancer. Curcumin is one such molecule that has been extensively explored against inflammation and is being recurrently studied against various types of cancer including leukemia with multiple mode of action, one amongst them being via histone methylation. However, the drawback of poor bioavailability profile restricts its drug status. Difluorinated chalcones and propanediones, owing to their structural similarity to the enol-keto form of curcumin, as well as to the plausibility of improved bioavailability due to fluorine atoms, seemed to bear appropriate candidature to be explored against histone methyltransferase in leukemia. These molecules were docked with 3K5K, G9a -UNC0224 crystal complex along with curcumin. Only after visible desired interactions, these molecules were subjected to enzyme inhibitory studies, considering BIX-01294 and curcumin positive control. 4-fluorine substituted di-fluorinated propanedione emerged as a potential inhibitor of histone methyltransferase highlighting 8-9% levels of methylation at 1 and 10 μM concentration. It showed significant apoptotic activity leading to G2/m arrest. In this study, we provide the first evidence that difluorinatedpropanedione is an inhibitor of histone methyltransferase and functionally involved in influencing cell proliferation and apoptosis in leukemic cell lines. The present studies on chalcones and propanediones herewith, showed that the di-fluorinated propanediones were more potent as compared to their chalcone counterpart. As also, the halogen substituted molecules proved to be more potential.
Title: Discovery and optimization of novel antagonists of the WDR5-MLL interaction
Drug Discovery Program at Ontario Institute for Cancer Research, Canada Department of Pharmacology and Toxicology, University of Toronto, Canada
Dr. Al-awar earned a PhD in synthetic organic chemistry from North Carolina State University working on Lycopodium Alkaloids and did a post-doctoral fellowship focused on natural products synthesis at the University of North Carolina at Chapel Hill prior to joining Eli Lilly and Company in 1995. While at Lilly, she was an active medicinal chemist in the oncology area working in multidisciplinary teams on the antimicrotubule agent Cryptophycin and later on several kinase focused efforts. In 2002, while at Lilly, Dr. Al-awar took on administrative responsibilities as Head in Discovery Chemistry Research and Technologies and later as Head, Route Selection, in Chemical Product Research and Development prior to joining the Ontario Institute for Cancer Research to build a Drug Discovery Program in July 2008.
Histone methylation is a key component of epigenetic signaling and transcriptional regulation. The Mixed Lineage Leukemia (MLL) genes encode a family of histone methyltransferases that activate gene expression through the methylation of histone H3 on lysine 4 (H3K4). Rearrangement and amplification of the MLL1 locus are drivers of leukemogenesis, accounting for 10% of AML in adults and nearly 70% of ALL in infants. In addition, MLL1 mutations are common in a variety of solid cancers, including breast, colon, lung, and bladder. WD40 repeat protein 5 (WDR5) is a component of the multiprotein MLL1 complex that is essential for its methyltransferase activity, and disruption of the WDR5/MLL1 interaction may therefore present a viable therapeutic option for the treatment of MLL-dependent leukemias. We conducted a medium throughput screen that identified micromolar drug like hits. Following several rounds of optimization using a structure-based approach and focused virtual library design we were able to identify OICR-9429, a nanomolar, highly selective and cell permeable inhibitor of the WDR5-MLL interaction. OICR-9429 is the first highly potent small molecule antagonist of the WDR5-MLL1 interaction and will serve as a valuable molecular probe for further exploration of WDR5 function.
Title: Homology modelling, structure- and ligand-based drug design of novel tubulin inhibitors and calcium channel blockers with anti- proliferative and leishmanicidal activities
Carlos Henrique Tomich de Paula da Silva
University of São Paulo, Brazil
Carlos Tomich is Associate Professor of Medicinal Chemistry, at School of Pharmaceutical Sciences of Ribeirão Preto (Brazil). He was born in Brazil, where he did all his studies including Chemistry (State University of Campinas), Master's (Military Engineering Institute), Ph.D. (University of São Paulo), two postdoctoral stages including the Barcelona Biomedical Research Park – Spain, at the Dr. Manuel Pastor´s group. In research, he works with Computational Medicinal Chemistry, with particular emphasis in cancer, Alzheimer's and inflammatory diseases. He has 1 patent and 137 publications (112 papers, 25 book chapters). He is also editor of 4 international books of Medicinal Chemistry.
Nowadays, the biggest challenge for the chemotherapeutic treatments and which is responsible for many cases of failures in both the cancer and the leishmaniasis treatments is called multidrug resistance (MDR). MDR is not only related to a class of medication or to a specific target, but it can also be related to the multiple factors involved in this process. The pathways that affect the decrease of drug concentration in the intracellular environment are related to the decrease associated with the inflow of the carriers, e.g. a diminution via the ABC superfamily (ATP-binding cassette) through the efflux caused by the action of P-glycoprotein (MDR1). Within the ABC superfamily, the P-glycoprotein (P-gp) is the most widely studied class and the calcium channel blockers class is the first generation of P-gp modulators. Moreover, they interfere with the adhesion of the parasite to macrophages and this could be an important strategy to control the initial phase of leishmaniasis. In this work, we carried out the design of drug candidates addressed to be selective against tumor cells, provided with anti-proliferative and leishmanicidal properties through inhibition of tubulin, and not suffering the MDR phenomenon. We have used Ligand-Based Drug Design (LBDD), Structure-Based Drug Design (SBDD), pharmacokinetic and toxicological (ADME/Tox) predictions, as well as homology modeling of a L-type calcium channel. Resulting model was well evaluated as the top- ranked amongst three other models based on two other structures detected in a previous Blastp search. The two drug design approaches above mentioned were then used to perform virtual screening in different commercial compounds databases, totalizing 15-20 compounds selected for purchase. In silico validations of the approaches here used were initially performed using small “contaminated” (with known active ones) databases, and our drug candidates were then validated in vitro, showing interesting bioactivity.
Title: Selective electrochemical determination of desipramine using a lipid modified carbon paste electrode
South Valley University, Egypt
Mahmoud Khodari Maeila Hamed is a Prof. of Analytical chemistry in South Valley University, Qena, Egypt. His education is B.SC. (general chemistry) at May 1980 Assiut University, Egypt, M.Sc. (Analytical chemistry) 1985, Assiut University and Ph.D at (Analytical Chemistry) 1990, ULB, Belgium- Assiut University, Egypt. His Publications are 54 in the field of analytical chemistry, drug analysis. He attended 21 conferences and meetings.
Carbon paste electrodes have been modified with some lipids for the sensitive and selective detection of the antidepressant (Desipramine). Voltammetric experimental conditions were optimized taking into account the importance of quantifying desipramine in the complex media and in the pharmaceutical formulations. The sensor(Lauric acid modified carbon paste electrode) responds to desipramine giving a cathodic current (at +0.88 V vs. Ag/AgCl electrode and pH 9). The response was characterized with respect to preconcentration potential, accumulation time, paste composition, possible interferences and other variables. A linear relationship between peak response and desipramine concentration over the range from 1 x10-7 to 1 x10-6 M. with standard deviation of 5.5 %.A detection limit of 3.3 x10-10M was obtained under the optimum conditions The method has been applied to the determination of desipramine in serum and urine samples.
Title: Antiviral acyclic nucleoside phosphonates: New structures and prodrugs
Czech Academy of Sciences, Czech Republic
Dr. Marcela Krečmerová studied organic chemistry at Charles University in Prague and defended her PhD. thesis at the Institute of Organic Chemistry and Biochemistry (IOCB) of the Czech Academy of Sciences in 1990.Most of her scientific cereer she has been working in the field of nucleoside and nucleotide analogues, many years in a close collaboration with Professor Antonín Holý, the founder of acyclic nucleoside phosphonate chemistry. Her research in the field of 5-azacytosine compounds resulted in development of a new class of extraordinary activeantivirals against DNA viruses.Recent investigations of Dr. Krecmerova are focused to development of prodrugs of biologically active molecules to improve their pharmacological properties and enable their future development as potential drugs.In 2012-2015 she was a head of the junior researchteam at the IOCB focused on developmentof novel therapeutics for cancer and viral diseases. She holds two patents and has co-authored 55 original scientific papers.
Acyclic nucleoside phosphonates (ANPs) belong to the most successful research topics in our Institute. Systematic investigations in this area resulted in three crucial antiviral drugs in medical practice: cidofovir, adefovir and tenofovir. Entering tenofovir and its therapeutic combinations (Truvada, Atripla, Complera, Stribild) to the market has the lion´s share on transformation of HIV/AIDS from the life-threatening emergency to a manageble chronic disease. Ourpresent research in the field is targeted not only to synthesis of new structures but also to improvement of pharmacokinetic properties of compounds already known. There aredozens of therapeutically attractive ANP structures never advanced to the stage of preclinical/clinical investigations. These compounds have usually sufficientantiviral activity but very low bioavailability caused by their polar character. The way to overcome this problem is synthesis of prodrugs. In this work, we present syntheses of various structural types of ANP prodrugs and comparison of their antiviral activities. These prodrugs are: amino acid ester phosphoramidates, POM and POC esters, alkyl and alkoxyalkyl esters, salicylic esters and (methyl-2-oxo-1,3-dioxol-4-yl) methylesters. We focus namely to two pharmacologically interesting ANP types: 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidines– so-called “open-ring” derivatives and to the group of 5-azacytosine acyclic nucleoside phosphonates,especially1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (HPMP-5-azaC) and1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (PME-azaC). HPMP-5-azaC and its cyclic form have been developed in our group as less toxic and more effective alternatives to cidofovir. The prodrug form, hexadecyloxyethyl ester of cyclic HPMP-5-azaC revealed the highest values of anti-DNA virus activities including imposing selectivity indices on the order of thousands, e.g. 1160 for herpes simplex virus (HSV-1), ≥5800 for varicella zoster virus (VZV) or ≥24600 for human cytomegalovirus (HCMV). The only disadvantage of HPMP-5-azaC is its complicated metabolic profile due to instability of the 5-azacytosine ring in alkaline conditions including physiological pH. Comparing stability of various 5-azacytosine ANPs, we found much better stability for another 5-azacytosine derivative, 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (PME-azaC). Despite the fact that antiviral activity of this free phosphonic acid was only marginalwe found promising antiviral activity in its prodrugs, especially against VZV and HCMV.It is another proof that some acyclic nucleoside phosphonates can increase their activities after transformation to prodrugs. Moreover, in some cases not only activity values but also the spectrum of activities could be influenced by transformation to prodrugs. This work was supported by the Subvention for development of research organization RVO 61388963 and the grant 14-00522S by the Grant Agency of the Czech Republic.
Title: Design and synthesis of benzoazoles incorporating fluorine and piperazine moieties with potential biological activities
Sultan Qaboos University, Oman
Abdel-Jalil, R. J. is Associate Professor in organic chemistry at the Department of Chemistry at Sultan Qaboos University. He was a postdoctoral research fellow in Crump Institute for Molecular Imaging at UCLA. Abdel-Jalil, R.J. earned his doctoral degree in Organic Chemistry at Tuebingen University, Germany under the auspices of German Academic Exchange Service (DAAD) Fellowship. He obtained a Master of Science degree and a Bachelor of Chemistry degree from the University of Jordan, Jordan. Abdel-Jalil is the authored/co-authored of over 40-refereed scientific articles as of May 2016. His research interests include development of new methods in organic synthesis, synthesis of biological active compounds and chemical modification of stationary phases. Abdel-Jalil has developed several new methods in chiral and achiral synthesis of heterocyclic systems.
Abstract The chemistry of heterocycles has emerged as a fundamental division of organic synthesis which is highly contributed to drug discovery. Structural modification of heterocycles comprises at least half of all organic chemistry research worldwide. Benzazoles,as one class of heterocycles,form the basis of many pharmaceutical, agrochemicals, veterinary, and natural products.Moreover, benzazole derivatives possess a diverse range of biological activities, which make them a good skeletons for drug design. The deisgned introduction of substituents on benzoazole can dramatically alter its biological activity. Fluorine and piperazine are common appendages in valuable therapeutic molecules in medicinal chemistry. For instance, ciprofloxacin® (1) is a powerful antibiotic with a broad spectrum of biological activity and its activity was related to the incorporation of fluorine and piperazine1. Previously, we have successfully synthesized several heterocycles2-4(2-4) and recently benzoazoles5(5-8) bearing fluorine and piperazine as shown in Figure 1.
Title: A Study of highly standardized aqueous extract of Terminalia chebula 250mg, 500mg versus Placebo in modifying cardiovascular risk with special reference to Endothelial dysfunction in patients with Type2 Diabetes Mellitus
Nizam’s Institute of Medical Sciences (NIMS), India
DNB (Clinical Pharmacology); MD (Pharmacol); FCCP; FIPS; PG Diploma Bioethics Usharani Pingali certified by NABH Accreditation board for accreditation of Clinical trials site, Ethics Committees and Investigators. She has more than 20 years of experience in clinical research. Guide to MD, DM and PhD students. She received a number of scientific awards including LK Oration in Sept 2012, she got UK Seth Gold medal for best research paper in clinical pharmacology; PP Suryakumari Medal for best research publication in diabetes, Ford Foundation Travel Fellowship, Minifellowship On Lipid Disorders training at Glastone Institute of Cardiovascular Sciences and Ati Vishisht Chikitsa Gold Medal from Association of College of Chest Physicians, New Delhi. Her fields of interests are Exploratory Phase I studies of new molecules, Developed non-invasive methods to evaluate the pharmacodynamic effects of drugs in early drug development phase, Scientific evaluation of drugs from herbal origin, Pharmacodynamic evaluation of drugs on endothelial function, Evaluation of drugs in diabetes, dyslipidemia and hypertension, Quality Assurance and Audit of clinical research projects. Specialized Area of Work: Worked in field of clinical pharmacodynamics for over 20 years with specific interest in evaluation of pharmacodynamic effect of drugs using non-invasive methods especially in relation to endothelial dysfunction. Developed and validated some techniques to study drug effects and mechanism of action of drugs especially on Endothelial function and cardiovascular effects, psychomotor performance, gastro-intestinal motility, pain, saccadic eye movement and other CNS effects etc. Worked extensively on herbal formulations also as there are very few systematically conducted studies on the pharmacodynamic effects. Instrumental in establishing ICMR Advanced Centre for Clinical Pharmacodynamics.
Background: Diabetes is associated with an increase risk of atherosclerosis including platelet hyper-reactivity increased inﬂammation, and endothelial dysfunction. Terminalia chebula (TC) is reported to possess antidiabetic, anti-oxidant, anti-inflammatory activity amongst others. The present study was thus undertaken to evaluate the effect of TC 250mg, TC 500mg versus Placebo on endothelial function in patients with type 2 diabetes. Methodology: After IEC approval and informed consent, eligible subjects were randomised to either–(1) one capsule of TC 250mg, (2) one capsule TC 500mg or (3)one capsule of Placebo, each given twice daily for 12 weeks. Subjects were reviewed at 4 weeks, 8 and 12 weeks of therapy. At each visit they were evaluated for efficacy and safety. Pharmacodynamic evaluation for endothelial function (change in RI) done at every visit. Blood samples were collected for evaluation of biomarkers (Nitric oxide MDA, Glutathione, hsCRP) Lipids and safety lab tests before and at end of treatment. ANOVA and t Test were used for statistical analysis by Prism Graphpad. Results: Of 74 screened, total 60 eligible subjects completed the study, twenty in each group. Significant reduction in RI was noted with TC 250mg (−2.38±0.82% to −4.93±1.87% ; p<0.001) and TC 500mg (−2.35%±0.85% to −6.14%±1.01%;p<0.001) suggesting improvement in endothelial function compared to baseline and placebo (-2.11+1.61 to -1.01+2.05%). Significant improvement noted in biomarkers of oxidative stress and systemic inflammation with TC 250 and 500mg compared to baseline and placebo. All treatments were well tolerated. Conclusion: Both TC250 and 500mg significantly improved endothelial function and reduced biomarkers of oxidative stress without any significant changes in safety labparameters. Terminalia chebula 500mg twice daily produced more pronounced response on pharmacodynamic parameters of endothelial function and biomarkers of oxidative stress as evidenced by significant reduction in mean RI index and improvement in nitric oxide, Glutathione and hsCRP compared to TC 250mg and placebo.
Title: Structure-affinity and structure-kinetics relationship study: A new combination strategy in medicinal chemistry
Xuzhou Medical University, China
Dong Guo, PhD obtained his PhD degree from Leiden University, The Netherlands, in 2014. Since then, he has worked as a postdoc fellow at the same university within the K4DD (Kinetics for Drug Discovery) consortium, financially supported by Europe’s Innovative Medicines Initiative (IMI) program and major Pharma companies. In February 2016, he joined the Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy at Xuzhou Medical Universityin China. His main research interest is the investigation of ligand-receptor binding kinetics at G protein-coupled receptors, from both theoretical and experimental perspectives.
In the past decade drug research community has started to appreciate the indispensable role of ligand-receptor binding kinetics (BK) in drug discovery. Next to the classical equilibrium-based drug evaluation process with affinity and potency values as outcomes, kinetic investigation of the ligand-receptor interaction can aid compound triage in the hit-to-lead campaign and provide additional information to understand the molecular mechanism of drug action.To this end, we performed an extensive structure-kinetics relationship (SKR) study in addition to a traditional structure-activity relationships (SAR) analysis at a prototypical drug target—the adenosine A2A receptor (A2AR). The ensemble of 24 antagonistsdisplayed only minor differences in affinity, while they varied substantially in their binding kinetics at the target. Such a combination of SKR and SAR analysis will have general importance for medicinal chemistry efforts on other drug targets as well.
Title: Synthesis, anti-Inﬂammatory, analgesic, molecular modeling and admet studies of diclofenylalanylhydrazide
Magda Hassan Abd El Lattif
Taif University, Kingdom of Saudi Arabia
Magda Hassan Abd El lattif is an assistant professor of pharmaceutical organic chemistry in Pharmacy college, Head chairman of pharmaceutical chemistry department, Deanship of scientific research at Taif University, Kingdom of Saudi Arabia. She is also a Consultant of forensic chemistry, Medicolegal institute, Egypt and also is an Expert of Narcotics and Drugs, Tiaft, USA.
The present work aims to synthesize novel diclofenac derivatives containing L-alanine moiety. The synthesized compounds docked into the active site to discover validated inhibitors of cyclooxygenases (COX-1 and COX-2). The calculations in-silico were predicted that, the compound with lowest energy of docked poses was interacted with residues of active site, perhaps could be making them possible selective inhibitors against (COX-2) and physiologically active. The binding score of compound compared with reference drug, and show extensive interactions with the targets, which may consider it a suitable selective inhibitor against (COX-2). Keywords: ALANINE, DICLOFENAC, COX, DOCKING, ADMET.
Title: Synthesis of zinc oxide doped- poly(8-anilino-1-napthlene sulphonic acid) (ZnO/PANSA) as conducting platforms for TB drug biosensors
University of the Western Cape, South Africa
Dr Ajayi is a senior lecturer at the Chemistry Department and a research leader at the Enzyme Sensor Laboratory, SensorLab at the University of the Western Cape (UWC). She teaches Physical Chemistry at second, third year and honours level and is involved in postgraduate research supervisions. At SensorLab she specializes in research that involves the development of drug (particularly HIV and TB treatment drugs) metabolism biosensors and the synthesis of various conducting polymeric and metallic nanomaterials. DrAjayi is the recipient of various grant awards and has research collaborations in South Africa, France and the US.
In this study we described a potential isoniazid (INH) biosensor platform based on zinc oxide doped- poly(8-anilino-1-napthlene sulphonic acid) (ZnO/PANSA) as a diffusional mediator and N-acetyltransferase (NAT2) on gold electrodes. To acknowledge the health complications amongst TB diagnosed patients as a result of the inappropriate dosing of isoniazid; devices with fast response times with enhanced performances and increased sensitivities are essential. This study reports the synthesis and characterization of electroactive platforms for application in the development of nanobiosensors suitable for the appropriate dosing of clinically diagnosed patients by promptly quantifying the levels of the TB drug Isonaizid.
Title: Role of Formyl Peptide Receptors in the Regulation of Thrombosis and Haemostasis
University of Reading, UK
Maryam Salamah is a postgraduate researcher at the University of Reading working under the supervision of Dr Sakthivel Vaiyapuri. Her research currently focuses on the effects of formyl peptide receptors in the regulation of platelet function. She received her master’s degree in Biomedical Sciences from the University of Brighton, in which she had the chance to work at the Royal Sussex County Hospital to establish a technique for hematological diagnostic tests. She also obtained a certificate in Medical Laboratory Technology from King Abdulaziz University, where she had the chance to work as a laboratory technologist at various laboratories in King Abdulaziz University Hospital and King Faisal Hospital & Research Centre (KFH&RC).
Platelets are small circulating blood cells that play a pivotal role in the regulation of haemostasis by preventing excessive bleeding through blood clotting. In appropriate activation of platelets under pathological conditions leads to the formation of blood clots (thrombosis) within the blood vessels resulting in life-threatening conditions such as heart attacks and strokes. Moreover, due to their high number in the circulation, platelets play a significant role in the progression of inflammatory responses. Although currently used anti platelet drugs help save lives, they are associated with severe side effects such as bleeding and they are ineffective in some patients. This emphasizes the need for the development of safer and more effective therapeutic strategies for the prevention and treatment of cardiovascular diseases. Platelets possess formyl peptide receptors (FPRs), which were originally found on leukocytes where they play indispensable roles in the regulation of host defense and inflammatory responses. The expression of these receptors has been previously reported in platelets and their stimulation induces chemotaxis and calcium release in platelets. Together, these results suggest that the FPRs play a role in the regulation of platelet activation. However, the detailed characterization of these receptors in the regulation of platelet function has not been established yet. Therefore, in this study, we aim to determine the role of FPRs in the regulation of thrombosis and haemostasis using a range of in vitro and in vivo platelet functional assays. Furthermore, the regulatory mechanisms that control the functions of FPRs in platelets will also be established. Our preliminary data support our hypothesis that FPRs play significant role in the modulatioof platelet function. We confirmed the expression of FPR1 in human platelets by transcriptomics and immunoblot analyses. In addition, the flow cytometry analysis indicates that the level of FPR1 is increased upon activation of platelets with an agonist. This suggests the presence of FPR1 in platelet granules. FPR1 agonists such as fMLF induced platelet activation in a dose-dependent manner and this was inhibited when FPR1 antagonists were used. In addition, a selective FPR1 antagonist, cyclosporin H inhibited platelet activation induced by agonists such as CRP-XL and this suggests that FPR1 mediated inverse signaling may impact on the regulation of platelet functions. Together these data demonstrate potential roles for FPRs in the regulation of platelet activation and therefore in thrombosis, and haemostasis.
Title: Cytotoxic effects of bioactive compounds isolated of Iris persica L. on human cancer cell lines
Faiq H. S. Hussain
University of Salahaddin-Erbil, Iraq
Faiq H. S. Hussain was born 1953 at Sulaimani city, Kurdistan region, Iraq. He successfully awarded B.Sc. in Chemistry 1976, M.Sc. in Organic chemistry 1978 and Ph.D. in Organic chemistry at Manchester university-UK 1985. He is senior of Organic chemistry at Chemistry department, University of Salahaddin-Erbil. He was Head of Chemistry Department 1992-1998 at college of science, Salahaddin university-Erbil. He has 30 publications in international and local journals. He supervised 21 master students and 8 Ph.D. students in his career. Head of Research group of PROKURUP project, University of Pavia-Italy, 2011 to date with Prof. Giovanni Vidari at department of Organic chemistry.
Genus Iris (Iredaceae) comprises over 300 species; 12 of them are present in Iraq. Iris persica has been used in Kurdish traditional medicine for the treatment of wound inflammation and tumor. However, Chemical and biological aspects of I. persica have not yet been investigated. The present study reports the first investigation on the isolation and characterization of bioactive compounds from flowers, bulbs and rhizomes of I. persica that has been collected from Kurdistan Region-Iraq and cytotoxicity effect of the isolated compounds against six human cancer cell lines were evaluated. Dry flowers, bulbs and rhizomes of I. persica were exhaustively extracted by maceration at room temperature, solvents of increasing polarity: hexane, methanol, methanol/water 70:30. Chlorophylls were removed from the methanolic extracts of flowers by filtration on a C-18 reversed phase column. Subsequently, the methanolic extracts of the flowers, bulbs and rhizomes were separately fractionated by repetitive preparative MPLC, on C-18 reversed phase, affording four compounds as the major products: tectorigenin (1), embinin (2), isovitexin (3) and trans-resveratrol-3-O-β-D-glucopyronoside (4). The structures of the compounds were identified on the basis of spectroscopic analyses and comparison with literature data. (1) (2) (3) (4) The cytotoxic activity was measured against six human cancer cell lines, the effects of two isolated compounds, Tectorigenin (1) and embinin (2), on the proliferation of tumor cells were evaluated in comparison with the well-known antitumor drug cis-diamminedichloroplatinum(II) (cisplatin) by MTT assays. In particular, MCF7 and SkBr3 breast, endometrial Ishikawa, ovarian BG-1, mesothelioma IST-MES1 and lung A549 cancer cells were treated for 48h with increasing concentrations of tested compounds. Compound P2 showed a stronger inhibitory activity than cisplatin in five cell lines from total of the six cell lines; MCF7, SkBr3, Ishikawa, BG-1, IST-MES1 and A549, embinin IC50 ± S.D of 6 (±3), 4(±1), 10(±3), 8(±2), 7(±2) and 9(±1) µM. while cisplatin (standard) IC50 ± S.D of 17(±4), 10(±2), 10(±3), 12(±3), 12(±2) and 13(±2)µM respectively. In conclusion, this is first study on phytochemical study of I.persica as well as cytotoxic acitivity of embinin isolated flowers of I.persica, this study confirms that Embinin could be considered as a natural anticancer. At the same time, the present study confirms the traditional use of Iris persica L. in the treatment of tumor.
Title: A practical and eco-friendly synthesis of oxo-bile acids
Pusan National University, Republic of Korea
Hwayoung Yun did his undergraduate work at Seoul National University. He have intensively experienced the synthesis of complex small molecules through the studies on total synthesis of various natural products such as macrolides, alkaloids, iridoids, macrolactams and polypeptides. A range of academic training and an in-depth research experience have provided he with considerable expertise in biomedical disciplines including synthetic organic, medicinal chemistry and chemical biology. His ultimate research interests are the discovery of bioactive small molecules as selective regulators of intracellular signaling pathways and investigation of their biological mode of action.
Oxo-bile acids are useful cholic acid derivatives with promising properties and have bothmedical and pharmaceutical applications. They are one of the most important intermediatesfor the synthesis of ursodeoxycholic acid (UDCA), which is currently the only product approved by the US FDA for the treatment of primary sclerosing cholangitis. However, large quantitiesof UDCA cannot be obtained from natural sources. For this reason, commercialUDCA is produced by the chemical manipulation of plentiful primary bile acids suchas cholic acid and chenodeoxycholic acid. In these chemical transformations, criticaloxidation steps are required steps for the practical syntheses of oxo-bile acidintermediates. In many cases, toxic heavymetal-based oxidizing agents have been used in spite of their toxicity.From the greenchemistry standpoint, the utilization of less harmful agents is always desirable andindeed there have been efforts to develop more eco-friendly conditions for the synthesisof oxo-bile acid derivatives. In this connection, we describe the applicationof a cerium-catalyzed oxidation to secondaryalcohol groups of bile acids in the hope of developing a more versatile and greenermethod for the preparation of various oxo-bile acids.
Title: Synthesis and cellular uptake of nanocomposites containing oligonucleotides and their analogues immobilized on inorganic nanoparticles
Novosibirsk State University, Russia
Marina N. Repkova was born in Kronshtadt, Russia. She received the MS degree in chemistry from Novosibirsk State University, Russia, in 1979 and the Ph.D. degree in bioorganic chemistry from Novosibirsk Institute of Bioorganic Chemistry in 1999 (Russia). From 1979 to present, she has been Postgraduate Student, then Research Scientist, with the Laboratory of Nucleic Acids Chemistry from Novosibirsk Institute of Bioorganic Chemistry (then Institute of Chemical Biology and Fundamental Medicine) of Siberian Branch of Russian Academy of Sciences. She is the author of more than 100 articles and more than 10 patents. Her research interests include the synthesis of Oligonucleotides and their derivatives and the synthesis of nucleic acid-based nanocomposites and their delivery into cells. Currently she works at the Novosibirsk State University.
The development of efficient and convenient systems for the delivery of nucleic acid-based drugs into cells is an urgent task. Despite many efforts in this field, this problem cannot be considered as completely solved. А promising way is the use of various nanoparticles. We developed methods of immobilizing DNA fragments to titanium dioxide nanoparticles with the formation of TiO2~DNA nanocomposites. Three forms of TiO2 nanoparticles (amorphous, anatase, and brookite) were used for the construction of nanocomposites. Two approaches to the preparation of nanocomposites are described: 1) noncovalent sorption of oligonucleotide-polylysine conjugates onto TiO2 nanoparticles, and 2) the electrostatic binding of oligonucleotides to TiO2 nanoparticles precovered with polylysine. Both methods provide an efficient and strong immobilization of DNA fragments onto nanoparticles that lead to nanocomposites with a capacity of up to 60 nmol/mg for an oligonucleotide. Different types of oligonucleotides and their analogs can be immobilized on TiO2 nanoparticles, including single and double stranded DNA and RNA fragments of different length, oligo-2’-O-methyl-ribonucleotides, phosphorothioate oligonucleotides, and recently described 2’-O-methylribonucleotides with charge-neutral phosphoryl guanidine groups, as well as peptide nucleic acids. It was shown that oligonucleotides in nanocomposites retain their ability to complementary interactions. Independently of the form of nanoparticles and the immobilization method, the nanocomposites were demonstrated by confocal microscopy to penetrate into eukaryotic cells without any transfection agents and physical impact. It should be emphasized that a significant part of nanocomposites was internalized in cell nuclei. The proposed nanocomposites can be considered as an efficient approach to deliver oligonucleotides and their analogs into cells. “The work was supported by the grant of Russian Scientific Foundation no. 16-15-10073.”
Title: Apoptosis versus autophagy in the molecular mechanism of action of plant derived chemotherapeutics against hepatocellular carcinoma cells
Rajiv Gandhi Centre for Biotechnology, India
Greeshma Tom is pursuing PhD in Biotechnology under the guidance of Dr. Asha V. V., Scientist EII, Plant based bioactives and disease biology Lab, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India. She works on the evaluation of various cell death pathways activated during chemotherapy against liver cancer. Prior to doing PhD, she completed her graduate and post graduate degrees from Bangalore University and M.G University, India. She was awarded Research Fellowship by CSIR (Council of Scientific and Industrial Research) in 2012. She has published in peer reviewed journals with her colleagues at RGCB and presented papers in international conferences.
Hepatocellular Carcinoma (HCC) is the fifth commonest malignancy worldwide. There is an obvious critical need to develop improved methods for chemoprevention and treatment of HCC as the current strategies are ineffective. Naturally occurring phytochemicals and dietary compounds have emerged as promising molecules with chemopreventive and chemotherapeutic potential in different types of cancers. Recently, autophagy has emerged as a potential target in cancer chemotherapy, but its precise role being controversial. The study intends to investigate the role of autophagy in cell death induced by selected anticancer lead molecules (resveratrol, silibinin, glycopentalone) from plants in HCC cells. The anticancer agents were validated for their cytotoxic activity in HCC cell lines HepG2 and Hep3B. Chromatin compaction was characterized by Hoechst staining and cell cycle arrest by FACS analysis, which affirmed the activation of apoptosis. Our studies demonstrated that the selected anticancer agents induced autophagy together with apoptosis, dose and time dependently. Activation of autophagy was evidenced by fluorescence microscopic detection of autophagic vacuoles, formation of acidic vesicular organelles (AVOs), immunoblotting patterns for conversion of LC3-I to LC3-II, immunofluorescence analysis of recruitment of LC3-II to the autophagosomes and autophagic flux analysis using Bafilomycin A1. Also, the pathways regulating autophagy were analysed which revealed the involvement of PI3/Akt/mTOR pathway. The antagonistic roles of autophagy and apoptosis in response to exposure of HCC cells with these agents were evident through morphological and autophagy inhibition studies. Combining autophagy modulators with plant derived anticancer lead molecules would be an exciting modality for combating the worries of liver cancer.
Title: Anti-inflammatory action through inhibition of NF kB activation and translocation by band-2 isolated from Tinospora cordifolia(Thunb.) miers. in LPS stimulated RAW 264.7 cell lines
Rajiv Gandhi Centre for Biotechnology, India
Sheena Philip is a Ph. D student under Dr. Asha V. V, Scientist E-II, in Plant based bio-actives and disease division at Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India. Her research work mainly focus on the isolation of bio-active molecules from herbals directed against chronic inflammatory conditions. Prior to joining as a Ph. D student, she has qualified for CSIR fellowship and she also holds a master’s degree and Bachelor’s degree in Biochemistry from the University of Calicut. She has published in peer reviewed journals and presented papers in international conferences.
Although inflammatory barrier is a critical defensive mechanism, exaggerated responses(chronic inflammation) of innate inflammatory cells, eg. macrophages, dendritic cells etc, produce serious damage leading to cancer, atherosclerosis, arthritis, diabetes and septic shock. Since inflammation involves multiple proinflammatory mediators and pathways that lead to a wide range of changes in pathology, it is difficult to target the desired area when treating inflammation. The current treatment involves use of non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids which exert effect mainly through blockage of cyclooxygenases (COX). Of the two isoforms of cyclooxygenases (PGE2 poducing enzyme-COX), COX-1 is the constitutively expressed form required for physiologic functions and COX-2 is induced during inflammatiom. Selective COX-2 inhibition can avoid most of the toxic effects of NSAIDs like gastric erosion,inhibition of platelet aggregation etc. to an extent. Macrophages, the major inflammatory cell type, release cytokines, ROS, growth factors,chemokines, TNF-α, interleuckin-1 and MCP-1, PGE2 in response to activation signals (LPS,TNF-α) through the canonical NF kb pathway activation. So NF-κB and the signalling pathways have become a focal point for intense drug discovery. Also inactivation of MAPKs might inhibit inflammatory mediators (NO and PGE2), making them potential targets for anti-inflammatory therapeutics. Tinospora cordifolia is well known for its anti-inflammatory potential in several invivo models, but the underlying molecular mechanism or the phytochemisry remains unknown. The isolated fraction inhibits the production of TNF-α,PGE2 and NO through cox-2 selective inhibition of p65 translocation and p38 phosphorylation. Characterization of this particular fraction will be beneficial in the treatment of chronic inflammatory condition without extensive side effects.
Title: Identification of structural elements of MCP chemokines and their shared receptor CCR2
Zil e Huma
Monash University, Australia
My name is Zil e Huma and I am a final year PhD scholar in the Department of Biochemistry and Molecular Biology at Monash University, Australia. In addition, I am also working as a teaching associate at the same department. My area of interest revolves around understanding the signalling mechanisms of GPCRs. Chemokines and their receptors have always been a target of interest because of their role in inflammatory diseases. I am interested to investigate different chemokines which cause differential signalling at the same receptor. This study will help understand the chemokine-receptor interactions to develop novel therapeutic agents.
Chemokine receptors are G-protein coupled receptors (GPCRs) that regulate the movement of leukocytes during inflammation. CCR2, a major chemokine receptor on monocytes and macrophages, binds to several CC chemokine ligands and plays a key role in atherosclerosis, obesity and type 2 diabetes.The major ligands of human CCR2 include monocyte chemoattractant protein 1 (CCL2) and MCP-3 (CCL7).Here we show that MCP-1 and -3 have distinct potencies and efficacies of signalling at CCR2 and we identify structural features of the chemokines and receptor contributing to the differences.First, using a series of chemokine chimeras, constructedby swapping the three main receptor recognition regions between MCP-1 and MCP-3,we have identified structural elements of MCP chemokines responsible for differences in receptor activation.We found that the chemokine N-terminus plays a major role towards full versus partial agonism.The affinities of the chemokine chimeras to the CCR2 also confirmed that the N-terminus makes a significant contribution to receptor binding by these two chemokines.Second, using a series of CCR2 mutants, we have identified elements of CCR2 that interact preferentially with the chemokines. The affinity of chemokine binding and the potency of ERK-1/2 phosphorylation by MCP-1 and MCP-3was determined for each receptor mutant. Four of the mutants, Y120F, R206A, I263A/N266A and Y259F displayed differential effects on the affinity of MCP-1 relative to MCP-3. These mutated residues are clustered together in the transmembrane region of the receptor.We conclude that this region of the receptor plays a major role in distinguishing between the two cognate chemokines, apparently by differential interactions with the N-terminal regions of the chemokines.Our investigation has yielded significant new information on chemokine receptor binding and signalling, which will guide future drug development.
Title: Characterization of nucleotide pool in bacterial cells
Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences v.v.i., Czech Republic
After the period of pesticide analysis in certified laboratories, I switched to medicinal chemistry and continue working with liquid chromatography and mass spectrometry techniques. After several years, I have started PhD studies. Modern analytical chemistry is my hobby and could be often quite challenging. 2003-2008: Faculty of Food and Biochemical Technology , UCT, Prague 2008: National Veterinary Institute, Prague 2009-2010: Institute of Organic Chemistry and Biochemistry, CAS 2010-now: Institute of Organic Chemistry and Biochemistry, CAS; Charles University, Department of Analytical Chemistry, Prague; Ph.D.study
Various bacterial responses to environmental stimuli lead into changes in intracellular concentration of small molecules (nucleotides, nucleosides and their derivatives). Robust, sensitive and simple method for characterizationof thesechanges is therefore necessary.E.g. in the case of stringent response –a potential novel drug target - intracellular levels of alarmone nucleotides guanosine tetraphosphate (ppGpp) and pentaphosphate (pppGpp), need to be determined. There are two key steps in the process of determining nucleotide levels in bacterial biomass (complex samples with strong matrice effect):1) extraction method with quantitative and reproducible yield, and 2) good analytical method capable todistinguish and quantify individual nucleotides. To characterize nucleotide pools in bacteriawe have chosen LC-MS in HILIC mode of separation that exhibits many advantages over commonly used ion pair (IP) LC coupled with UV-VIS detector. Moreover, the ballast mass from bacteria are well separated from majority of analytes and do not disturb the analysis.
Title: Design TiO2 nanoparticles for using in nanocomposites containing oligonucleotides and their analogues
Novosibirsk State University, Russia
Elena V. Bessudnova was born in Sovetsk, Russia. She received the MS degree in chemistry from Southern Federal University, Russia, in 2007 and the Ph.D. degree in physical chemistry from Kemerovo State University, Russia, in 2014. From 2010 to present, she has been Postgraduate Student, then Research Scientist, with the Environmental Catalysis Laboratory from Boreskov Institute of Catalysis, Siberian Branch of Russian Academy of Sciences. She is author of more than 10 articles. Her research interests include the synthesis and design of nanoparticles and their study physico-chemical properties. Currently she works at the Novosibirsk State University.
Recent advances in nanomaterials made possible to tackle difficult problems, in particular, the application of titanium dioxide nanoparticles in biological tasks. The conditions required for biological experiments (neutral pH values and water-soluble state of nanoparticles) often lead to aggregation of nanoparticles and changes in their morphology. Low aggregation stability of extremely small nanoparticles and their toxic properties make it necessary to devise special methods for synthesis of nanoparticles aimed at improving their dispersion stability and biosafety. We designed TiO2 nanoparticles for using in nanocomposites with oligonucleotides and found ways for diminishing the toxicity of TiO2-NPs and increasing the dispersion stability of the sols in physiological media by optimizing the conditions of chemical treatment of TiO2 sols. The effect of the nature of singly charged electrolyte cation (Li+, Na+, K+, NH4+) used for neutralization of the initially acid TiO2 sols, a method of electrolyte introduction into sols, chemical nature of dialyzing solution, and surface modification of nanoparticles with isopropyl glycidyl ether (IGE) on the size of TiO2 particles at pH 6.5-7.5 and their cytotoxic properties was studied. Investigation of TiO2 sols dispersion by a set of physicochemical methods showed that chemical nature of the electrolyte cation affects sol agglomeration, which increases in a series Li+ > Na+ > NH4+, and the use of phosphate buffer for sol dialysis facilitates the formation of more uniform disperse systems. It was shown that the surface modification of TiO2 nanoparticles with IGE and using phosphate buffer diminishes its toxic effect on the cells and prevents undesirable interaction of TiO2 with cell components. TiO2 nanoparticles showed their potency as the basis of nanocomposites bearing DNA fragments for interaction with nucleic acid targets in cells.
Title: Low dose irbesartan has a renoprotective effect as high dose ramipril in diabetic rats treated with insulin
Abdulelah A. Thigah
Umm Al-Qura university, Saudi Arabia
Abdulelah A. Thigah was born on December 19, 1992 and live in mecca, graduated from Umm Al-Qura university with bachelor’s degree in medicine and surgery. interested in clinical researches and health promotion programs , looking forward to provide the best care and awareness to the community and to be one of the well known characters in his speciality as well as a great role model.
Objectives: The aim of this study is to compare the efficacy of the anti-angiotensin drug, ramipril and irbesartan on the vascular protection of kidneys of streptozotocin (STZ)-induced diabetic rats (DR). Methods: 110 male albino rats were divided into 7 main groups. Group-1 (10 normal control rats; NC). Group-2 (10 rats) was injected intra-peritoneally with STZ (Diabetic Rats; DR). Group-3 (10 DR) is controlled by insulin. Groups 4 to 7 (20 DR), each is subdivided into two subgroups that received either low or high dose of ramipril or irbesartan with or without insulin. Two months post treatment, rat-tail blood was collected to measure: Fasting blood sugar, HbA1c, total serum pro-teins, albumin and lipid profiles. Urine was collected to measure albuminuria. Kidneys were iso-lated for histopathological study. Results: Biochemically, both ramipril and irbesartan (without in-sulin) lowered albumin concentration in urine samples especially at high doses. Histopatholog- ically, there is no beneficial response of both drugs without insulin. Combination of insulin to- gether with either drug has beneficial effects biochemically and histopathologically at high doses. Low dose irbesartan only has renoprotective effect in DR treated with insulin. The other biochem- ical parameters showed negligible response to both drugs.Conclusion: Low dose irbesartan and high doses of both drugs have renoprotective effect in DR treated with insulin.
Title: Aspirin and blood glucose and insulin resistance
Abdullah A. Alshamrani
Umm Al-Qura university, Makkah, Saudi Arabia
Abdullah A. Alshamrani was born on February 25, 1992 in Jeddah-Saudi Arabia. Graduated from Umm Al-Qura (UQU) University in Makkah-Saudi Arabia with a bachelor's degree in medicine and surgery on June 2016. He currently work as a medical intern. . Interested in internal medicine and health awareness campaigns. Hoping to be a good doctor one day. Abdullah is currently resides in Jeddah-Saudi Arabia
Objective: A potentially important role of IKKβ in mediating insulin resistance and the ability of salicylates to inhibit IKKβ activity is suggested. We decided to examine the role of different doses of aspirin (low, moderate and high) in experimentally induced diabetic rats. Materials and Methods: Diabetes Mellitus (DM) in rats were induced by administration of nicotinamide (NAD), 15 min prior to the single dose of streptozotocin STZ i.p. Ninety male albino rats were used in this study. They were divided into 6 main groups. The first was served as control, which receives no medications. The second group was diabetic induced rats as mentioned above. The third group was controlled by insulin after induction of D.M. Groups from the fourth to the six consist of 20 diabetic induced rats and further subdivided into rats taking either aspirin alone in different doses (low, moderate or high) or aspirin and insulin. Results: Different doses of aspirin showed that moderate and to a greater extent high dose aspirin administration to diabetic rats have greater impact on fasting blood glucose levels whether treated with insulin or not. Again, HBA1c % in diabetic rats treated with insulin and receiving high dose aspirin was lower than diabetic rats treated with insulin only or even taking low dose aspirin. Conclusion: The study concluded that the inflammatory pathways hold a substantial part in insulin resistance in type 2 DM.
Title: Prevalence and preventive measures of infertility in male by kruger’s criteria, a randomized study in private and government health care hospitals
Jinnah University for Women; Pakistan
Background; Every single couple out of ten are in search of medical care because of infertility. Men older than 40 years and Women older than 30years are at an increased risk of infertility. Presence of Infertility can be both in males and females. The estimation of male infertility is frequently underestimated or delayed. They may also experience the history of testicular, prostate, or sexual problems. WHO guidelines reported that the man with a sperm count of <20 millions/ml is considered as 0oligospermia and nearly 100 million man around the world are surviving with erectile dysfunction. Symptomatic approaches steadily reducing the magnitude of couples classified as having idiopathic infertility. This is than perceived that no simple tests can conclude the probability of pregnancy in congregation in which the man is an infertile partner. Methods: A study has been designed and conducted to figure out existence, problems, and causes associated with infertility in men and treatment options. For this purpose, 33 patients (n=33) has been selected and investigated from different private and government health care hospitals. Results: Most of the patients are in the middle of their ages reported infertile. Primary infertility in infertile patients is 73% where as the presence of secondary infertility in the remaining respondent is 27%. Among all, 52% of the patients have co-morbid history of diabetes mellitus, 18% of them have issues about genitourinary trauma and infections, 30 patient have been identified problems related morphological count, 51% of them investigated abnormal volume of man semen. Evaluation of the study by Kruger’s strict morphology test reveals that over 75% of the men having insignificant infertility issues whereas 25% of them were observed significant infertility issues. Conclusion: It is concluded that male infertility is independent on the age factor whereas, excessive use of tobacco, alcohol, high fat food consumptions, obesity, heavy weight exercises, sedative life styles, contacts with chemical or toxins, stress or psychological disturbances might provoke issues of infertility in males. Key words: Infertility, semen analysis, Kruger’s strict criteria
Title: In silico pharmacokinetics and molecular docking of three leads isolated from Tarconanthus Camphoratus L
Amina I. Dirar
Aromatic Plants Research Institute, National Center for Research, Sudan
Objective: To investigate the pharmacokinetic and toxicity profiles and spectrum of biological activities of three phytochemicals isolated from Tarconanthus camphoratus L. Methods: Several integrated web based in silico pharmacokinetic tools were used to estimate the druggability of Hispidulin, Nepetin and Parthenolide. Afterward, the structural based virtual screening for the three compounds' potential targets was performed using PharmMapper online server. The molecular docking was conducted using Auto-Dock 4.0 software to study the binding interactions of these compounds with the targets predicted by PharmMapper server. Results: The permeability properties for all compounds were found within the limit range stated for Lipinski ׳s rule of five. Only Parthenolide proved to be able to penetrate through blood brain barrier. Isopentenyl-diphosphate delta-isomerase (IPPI), uridine-cytidine kinase-2 (UCK-2) and the mitogenactivated protein kinase kinase-1 (MEK-1) were proposed as potential targets for Hispidulin, Nepetin and Parthenolide, respectively. Nepetin and Parthenolide were predicted to have anticancer activities. The activity of Nepetin appeared to be mediated through UCK-2 inhibition. On the other hand, inhibition of MEK-1 and enhancement of TP53 expression were predicted as the anticancer mechanisms of Parthenolide. The three compounds showed interesting interactions and satisfactory binding energies when docked into their relevant targets. Conclusion: The ADMET profiles and biological activity spectra of Hispidulin, Nepetin and Parthenolide have been addressed. These compounds are proposed to have activities against a variety of human aliments such as tumors, muscular dystrophy, and diabetic cataracts. Keywords: Tarconanthus camphoratus L., Hispidulin, Nepetin, Parthenolide, In silico pharmacokinetic, Molecular docking, PharmMapper server, and Auto-Dock 4.0 software
Title: Zika virus NS5 protein potential inhibitors: An enhanced in silico approach in drug discovery
University of KwaZulu-Natal, South Africa
Pritika Ramharack is a PhD student under the supervision ofProf M.E. Soliman at the Department of Pharmaceutical Sciences, University of Kwa-ZuluNatal, South Africa. Her current research concentrates on the design of inhibitors against the Zika virus using in silico studies. She also has experience with molecular and cellular biology.
The re-emerging Zika virus is an arthropod-borne virus that has been described to have explosive potential as a worldwide pandemic. The initial transmission of the virus was through a mosquito vector, however, evolving modes of transmission has allowed the spread of the disease over continents. The virus already been linked to irreversible chronic central nervous system (CNS) conditions. The concerns of the scientific and clinical community are the consequences of Zika viral mutations, thus suggesting the urgent need for viral inhibitors. There have been large strides in vaccine development against the virus but there are still no FDA approved drugs available. Rapid rational drug design and discovery research is fundamental in the production of potent inhibitors against the virus that will not just mask the virus, but destroy it completely. In silico drug design allows for this prompt screening of potential leads, thus decreasing the consumption of precious time and resources. This study demonstrates an optimized and proven screening technique in the discovery of two potential small molecule inhibitors of Zika virus Methyltransferase and RNA dependent RNA polymerase. This in silico “per-residue energy decomposition pharmacophore” virtual screening approach will be critical in aiding scientists in the discovery of not only effective inhibitors of Zika viral targets, but also a wide range of anti-viral agents.