Day :
Session Introduction
Prakash Kinthada
Professor, JNTU University, India
Title: : Transition metal complexes/organometallic compounds as anticancer/anti HIV drugs or in pharmaceutical industry
Biography:
Dr.Prakash.M.M.S Kinthada, a Professor in the Department Of Chemistry at Sri Vidyanikethan Engineering college,Jawahar Lal Technological University,Anantapur,A.Rangam Peta, Tirupathi,INDIA.Earlier I was an AssociateProfessor in Chemistry ,GIT,GITAM University, Visakhapatnam, INDIA.
Abstract:
Cancer is a dreadful disease and any practical solution in combating this disease is of paramount importance to public health. Cancer patients have burdened by drug induced toxic side effects, and no turned to seek help from the complementary and alternative medicine hoping for a better cure. Research on Platinum based drugs and Non Platinum based drugs is a Multi-Million Dollar Industry in USA and there is every need to produce safe drugs for the cure of this monstrous disease. Flavonoids have a long history of use in traditional medicines in many cultures. The phytochemical, curcumin is one of the major dietary flavonoid, belonging to a group of flavonol, Curcumin is a natural polyphenol. It is highly potential molecule capable of preventing and treating various cancers. Various dietary chemo preventive agents, turmeric powder or its extract are broadly used as therapeutic preparations in Indian System of medicine. We provide a summarized synthesis and structural determination of Curcumin Oxime, Curcumin Thiosemicarbazone derivative of Gold (III) complex. The use of these analogs for prevention of cancer tumor progression and treatments of human malignancies. A pharmacologic agent for treating and/or preventing cancer, among other diseases and conditions, and particularly breast, prostate, and pancreatic cancer, in humans and animals. The novel pharmacologic agent is an isoflavonoid or isoflavonoid mimetic covalently attached to a cytotoxic pharmacophore that, preferably has the ability to conjugate with a metal salt to form a more potent metal complex, particularly a Au (III) complex and other complexes of Platinum, Palladium, Ruthenium, Copper etc.
- Molecular Modeling and Dynamics
Session Introduction
Nicolas Bocquet
leadXpro AG, Switzerland
Title: Structure based drug discovery on membrane protein targets
Biography:
Nicolas studied at the University of Compiegne (France) and completed his Engineer in Biotechnology degree. For his master and PhD in Neuroscience from the University Pierre et Marie Curie, he moved to the Pasteur Institute in Paris, where he worked in the group of Dr. Pierre-Jean Corringer and Prof. Jean-Pierre Changeux (Channel receptors group) on the elucidation of the crystal structure of a pentameric ligand gated ion channel in an open conformation. Starting February 2017, Nicolas will work on biophysical and structural biology programs within LeadXpro AG as a senior scientist.
Abstract:
Today, soluble proteins are managed routinely within the project timelines and scope with the rapid portfolio changes in pharmaceutical industry. Establishment of biophysical and structure-based methods for transmembrane proteins still represents a significant challenge to have an impact on drug discovery. leadXpro combines membrane protein expression, purification and structure determination coupled to premium access to the synchrotron Swiss Light Source (SLS), the Free Electron Laser (SwissFEL) and single particle cryo-electron microscopy (cryo-EM) at the University of Basel. LeadXpro also confronts structural data to different biophysical measurements like thermal shift assays, radiobinding assay and wave guide interferometry in order to generate better lead molecules with appropriate features.
The talk/poster will show advancements in projects and technologies with examples for serial crystallography performed at synchrotron and free electron laser enabling structure determination of challenging drug targets. Moreover, recent efforts and implementation of wave-guide interferometry method for analysis of small (fragment-like molecules)/large ligand binding kinetics on membrane proteins will be discussed in the context of i) lead discovery and optimization ii) biologics targeting membrane proteins. Finally, recent progress in cryo-EM will also be discussed.
- Structural Biology
Session Introduction
Ahmed Aly Ahmed Allam
Professor, Beni-Suef University Egypt
Title: Microstructure of scales in selected lizard species
Biography:
AAhmed Aly Ahmed Allam, he has done his Ph.D in the year 2008 in Zoology Department, Faculty of Science, from Beni-Suef University, Egypt. The Ph. D. Degree in developmental biology and development toxicity in September 2008 and entitled by "EFFECT OF ACRYLAMIDE ON THE DEVELOPMENT OF NERVOUS SYSTEM IN ALBINO RAT" and present he is the Professor of comparative anatomy and embryology, Faculty of science, Beni-Suef university, Vice dean of faculty of special needs, -Suef university, Beni-Suef 62511, Egpt
Abstract:
In the present study, it was hypothesized that micromorphology of the surface of many lizard scales appears to mimic the topography of the habitat in which they live. Many authors have suggested that the microstructure of the superficial surface of scales have undergone important adaptations and have functional value in lizards. In this study, we investigated the variation and adaptation of the micromorphology and microstructure of the superficial surface of the dorsal and ventral scales from the mid-body region of Stellagama stellio (Agamidae), Stenodactylus petrii (Gekkonidae), Acanthodactylus boskianus (Lacertidae), Eumeces schneideri (Scincidae), Trachylepis quinquetaeniata (Scincidae), Scincus scincus (Scincidae), Varanus griseus (Varanidae), Chameleo chameleon (Chamaeleonidae). Skin specimens were prepared and analyzed using scanning electron microscopy. The dorsal and ventral scale surfaces had microstructure in the studied species and they exhibited unique patterns that somewhat resembled the topography of the microhabitats in which they lived. Similarity was detected in the three most related species, those having a common family, Scincidae. Ecomorphological relationships were detected between the dorsal and ventral scale microstructures and microhabitats. We conclude that environmental factors have observable influences on the microstructure of lizard scales.
Una Janke
University of Greifswald,Germany
Title: Conformational dynamics of integrin alpha IIb beta 3 and its relation to changes in protein structure
Biography:
Una Janke has studied Humanbiology at the University of Greifswald, with the main focus on Immunology. Currently, she is a PhD student in the group of Prof. Mihaela Delcea at the Institute of Biochemistry and uses biophysical tools to investigate the impact of mutations and environmental factors (e.g. ions, drugs) on activation and immunogenicity of platelet receptor integrin αIIbβ3.
Abstract:
The transmembrane protein integrin alpha IIb beta 3 (αIIbβ3) is involved in hemostasis, wound healing and clot formation. Intracellular as well as extracellular signals can cause inside-out or outside-in signaling, which leads to at least three different conformations: the bent (resting) state; the intermediate extended form; and the ligand-occupied active state. The conformational dynamics of the overall structure of αIIbβ3 during the activation process is possibly related to changes in protein secondary structure, which has not been studied until now in a membrane environment (e.g. liposomes). Moreover, αIIbβ3 is related to the autoimmune disease immune thrombocytpenia, where potential external triggers influence the antigenicity of the integrin by changing the protein structure. In this study we determined the drug-induced activation of αIIbβ3 and the relation to the structure of this protein reconstituted into liposomes. The combination of activation assays and the biophysical tools quartz crystal microbalance, surface plasmon resonance and circular dichroism spectroscopy show binding of the conformation-specific antibody PAC-1 (which recognizes the active integrin) to αIIbβ3-treated with clinically relevant drugs (e.g. quinine). However, insignificant changes in protein secondary structure were found. Molecular dynamics simulation (MDS) studies confirmed a globular hinge motion in the ectodomain of the integrin with minor changes in protein secondary structure. Our biophysical setup in combination with MDS can be applied to study transmembrane proteins under different conditions in a biomimetic system.
Ina Buchholz
University of Greifswald, Germany
Title: Posttranslational modifications of beta2-glycoprotein I alter its structural dynamics
Biography:
Ina Buchholz has studied Biochemistry at the University of Greifswald, with main focus on Analytical Biochemistry and Biophysics. Currently, she is a PhD student in the group of Prof. Mihaela Delcea at ZIK HIKE (Center of Innovation for Humoral Immune Responses in Cardiovascular Disorders). Ina Buchholz investigates blood- and non-blood proteins involved in autoimmune diseases and the impact of environmental factors (e.g. pH, ionic concentrations, temperature), mutations and post-translational modifications on protein structure and immunogenicity.
Abstract:
Beta2-glycoprotein I (beta2GPI) is a soluble blood protein (326 AA, 5 domains) exhibiting two main conformational states: the circular or closed conformation, where the first domain (DI) is bound to the last domain (DV) of the protein; and the linear or open conformation. In the open form, beta2GPI binds to phospholipid membranes via DV and this form is considered to play a crucial role in the autoimmune disease antiphospholipid syndrome (APS). Therefore, investigating the structural dynamics of this protein is of high interest. We investigated different post-translational modifications (PTM) of beta2GPI and studied the impact on its conformation with biophysical tools (e.g. atomic force microscopy, circular dichroism spectroscopy). Additional insights into the interaction of DI and DV were gained from molecular dynamic simulation studies. PTM 1: Lysine residue acetylation reveals a partial opening of beta2GPI dependent on the acetylation ratio used (Buchholz et al., PCCP 2018). These data indicate that lysines predominantly stabilize the closed conformation and in vivo acetylation via acetyltransferases could destabilize the closed form, leading to a facilitated opening of the structure. PTM 2: Enzymatic reduction of the C-terminal Cys288/Cys326 disulfide bond near the putative contact interface of DI and DV also initiates a conformational change of beta2GPI. Furthermore, disruption of this disulfide bond leads to loosening of a 22 AA flexible loop carrying lysine residues critical for phospholipid membrane binding. In summary, these PTM reveal a critical level of destabilization of the closed beta2GPI conformation and beta2GPI conformational change may have a large impact on APS disease.
Dr Cassandra Terry
London Metropolitan University, UK.
Title: Structural characterisation of proteins involved in neurodegeneration
Biography:
Cassandra completed her MRes from The University of St Andrews and PhD from The University of Sheffield both on protein structure. Cassandra worked as a researcher on protein structure and function at the Medical Research Council in Cambridge, AstraZeneca and University College London. Cassandra is now a Reader (Associate Professor) in protein pathology at London Metropolitan University. Cassandra has published a number of peer-reviewed articles in reputable journals, is a reviewer for several journals, is a guest lecturer at KCL and UCL, scientific advisor for Brain Bee charity, mentor for students at The University of Sheffield and The Girls Network.
Abstract:
Proteins need to maintain their correct structure in order to carry out specific biological functions. When proteins fold incorrectly (misfold) and are not cleared from the body, these proteins can accumulate and cause disease. Researching protein misfolding is crucial to understanding how misfolded proteins cause a number of debilitating and fatal diseases such as Alzheimer’s Disease, prion diseases (e.g. Creutzfeldt-Jakob disease), Parkinson’s disease and Type II Diabetes. There are no known cures or treatments for neurodegenerative disorders (such as Alzheimer’s or Parkinson’s disease) due to our limited understanding of protein misfolding mechanisms and the lack of detailed structures of these misfolded proteins. Recently however, much progress has been made in investigating the structures of some of these proteins using structural methods such as Cryo-Electron Microscopy (Cryo-EM) and Atomic Force Microscopy (AFM). Recent structures of misfolded prion proteins (PrP) isolated from prion-infected mammalian brain revealed a unique structure distinct from propagating assemblies of the Alzheimer’s proteins (amyloid-β, tau) and proteins involved in Parkinson’s disease (α-synuclein) that have been reported. More high-resolution structures of misfolded proteins involved in disease plus research into how and why proteins misfold are now urgently needed to move forward in developing future therapeutics.
- 3D- Structure Determination
Session Introduction
Srinivasan undararaj
Assistant Professor, Australian National University, Australia
Title: Structural plasticity between homo and heterodimeric IRF4-DNA Interactions
Biography:
Srinivasan sundararaj compelted his PhD in 2017 at Monash University, Australia and works as a Postdoctoral research fellow under the supervision of Associate professor Marco Casaratto at the Australian National University. He specializes in structural biology and molecular interaction techniques and investigates the mechanistic basis of medically relevent protein complexes involved in immune regulation and tumour immunity. He has published his work as a lead author in several reputed journals including Nature communications and PNAS. Currently, he is also co-supervising and mentoring PhD students and also seving as a peer reviever for BMC biochemistry and Protein Science Journal.
Abstract:
Interferon regulatory factor 4 (IRF4) is a transcription factor (TF) that regulates the gene expression of immune cells including T cells and B cells. Due to its critical role, IRF4 is linked directly to numerous immune-related disease conditions including B cell-related chronic lymphocytic leukemia (CLL) and adult T cell leukemia (ATL). Structurally, IRF4 consists of two conserved domains; an N-terminal DNA binding domain and C-terminal IRF-association domain and binds the target DNA as either homo or heterodimer. Notably, it binds the canonical interferon-stimulated response elements (ISRE) DNA motif as a homodimer and regulates genes involved in interferon stimulation. Despite the significance of this association, the mechanistic basis underpinning this pivotal molecular interaction remains unknown. Through X-ray crystallography and surface plasmon resonance, we now provide the structural basis of this interaction. Our study identified a head to tail orientation in IRF4-ISRE interaction, with each monomer docking the opposite face of the DNA. We also found a substantial bending in DNA to accommodate α3 recognition helix directly on the major groove with no observed intermolecular interaction between the bound monomers. This markedly contrasts heterodimeric form where DNA bound IRF4 is shown to physically interact with other TFs. Notably, we also identified that the disease-causing mutations could bind directly to DNA as evidenced by their tighter binding affinities. Together, our study provides a structural snapshot of IRF4 homo and heterodimers and its role in regulating the target gene expression thereby providing insights into the basis of IRF4 mediated CLL and ATL pathogenesis.
- Structural Enzymology
Session Introduction
Shuntaro Hara
Showa University School of Pharmacy, Japan
Title: Expression and Characterization of Recombinant Human Acyl-CoA Synthetase ACSL4
Biography:
Shuntaro Hara received his M.S. and Ph.D. degrees from the University of Tokyo and started his research career as a postdoctoral fellow at the University of Tokyo. After postdoctoral training, Dr. Hara has worked as a research associate at the National Cardiovascular Center Research Institute (Osaka, Japan), as a visiting fellow at University College London, and as an assistant professor at Kitasato University (Tokyo, Japan), and then became a professor at the School of Pharmacy, Showa University in 2009. He has published more than 100 papers in reputed journals.
Abstract:
Acyl coenzyme A synthetase long-chain family members (ACSLs) are a family of enzymes that convert long-chain free fatty acids into their acyl-CoAs. Among ACSL isozymes, ACSL4 has been hypothesized to modulate the metabolic fates of polyunsaturated fatty acids including arachidonic acid. In the present study, to investigate the enzymatic and protein characteristics of ACSL4, the cDNA for human ACSL4 was cloned from human epithelial colorectal adenocarcinoma Caco-2 cells and then recombinant ACSL4 enzyme containing a C-terminal His-tag was expressed in Spodoptera frugiperda 9 (Sf9) cells using the baculovirus expression system. ACSL4 enzyme activity was detected in 10,000 x g supernatants of ACSL4-expressing Sf9 cell lysates and then partially purified by nickel affinity column chromatography. We further investigated the substrate specificity of recombinant human ACSL4 by LC/MS and found that ACSL4 enzyme preferred various kinds of polyunsaturated fatty acid including docosahexaenoic acid, docosapentanoic acid, eisopentaenoic acid, and dihomo-γ-linolenic acid, as well as arachidonic acid as a substrate. On the other hand, oleic acid, linoleic acid and linolenic acid were poor substrates, although these fatty acids contain unsaturated bonds. These results confirmed the importance of ACSL4 in maintenance of membrane phospholipid bearing polyunsaturated fatty acid.
- Structural Bioinformatics
Session Introduction
Mahesh Chandra Patra
Ajou University, Suwon, Korea
Title: Mechanism of phosphatidylinositol-dependent membrane localization of Toll/interleukin 1 receptor domain-containing adaptor protein
Biography:
Mahesh Chandra Patra is currently pursuing PhD degree at Ajou University, Suwon, Korea in the field of computational biology. He holds a Master’s degree in Bioinformatics from Orissa University of Agriculture and Technology, Bhubaneswar, India. He has expert level knowledge of molecular dynamics simulations and python programming language. He has published 25 papers including two review articles in reputed journals. Currently, he is developing a database for therapeutically relevant clinical/preclinical agents of innate immune signaling pathways.
Abstract:
The Toll/interleukin 1 receptor (TIR) domain-containing adaptor protein (TIRAP) regulates Toll-like receptor (TLR) 2, TLR4, TLR7, and TLR9 signaling pathways. TIRAP anchors to phosphatidylinositol (PI) 4,5-bisphosphate (PIP2) on the plasma membrane and PI (3,4,5)-trisphosphate (PIP3) on the endosomal membrane and assists in recruitment of the myeloid differentiation primary response 88 protein to activated TLRs. To date, the structure and mechanism of TIRAP's membrane association are only partially understood. Here, we modeled an all-residue TIRAP dimer using homology modeling, threading, and protein-protein docking strategies. Molecular dynamics simulations revealed that PIP2 creates a stable microdomain in a dipalmitoylphosphatidylcholine bilayer, providing TIRAP with its physiologically relevant orientation. Computed binding free energy values suggest that the affinity of PI-binding domain (PBD) for PIP2 is stronger than that of TIRAP as a whole for PIP2 and that the short PI-binding motif (PBM) contributes to the affinity between PBD and PIP2. Four PIP2 molecules can be accommodated by distinct lysine-rich surfaces on the dimeric PBM. Along with the known PI-binding residues (K15, K16, K31, and K32), additional positively charged residues (K34, K35, and R36) showed strong affinity toward PIP2. Lysine-to-alanine mutations at the PI-binding residues abolished TIRAP's affinity for PIP2; however, K34, K35, and R36 consistently interacted with PIP2 headgroups through hydrogen bond (H-bond) and electrostatic interactions. TIRAP exhibited a similar interaction pattern and binding affinity with PIP3 as it did with PIP2 through an H-bond network involving K34, K35, and R36. The present study enabled us to understand the mechanism of TIRAP's membrane association that can be useful for designing peptide-based drugs targeting TLR2-, TLR4-, TLR7-, and TLR9-mediated autoimmune diseases.
- Drug Designing
Session Introduction
Sergio Senar
DrTarget, Spain
Title: Machine learning applied to biomedical research
Biography:
Sergio Senar has completed his PhD at the age of 28 years from Alcalá de Henares University and postdoctoral studies on GPCR orphan receptors from SmithKline Beecham Natural Products Research Department. After a long career supporting early drug discovery at GSK he became self-employed at DrTarget, a non-profit Bio-Soft service entity devoted to consultancy on early portfolios for academy and pharma industry. He has published articles on signal transduction, drug discovery and mechanistic biochemistry.
Abstract:
The use of computational tools in the early stages of drug development has increased in recent decades. Machine learning approaches have been of special interest , since they can be applied in several steps of the drug discovery methodology, such as prediction of target structure, prediction of biological activity of new ligands through model construction, discovery or optimization of hits, construction of models that predict the pharmacokinetic and toxicological (ADMET) profile of compounds, and assessment of mechanism of action and identification of new targets for further research. .
Two public domains, NCBI and ChemBl hold millions of experimental records accessible to the whole biomedical community. The websites support applications to facilitate access to results for limited number of assays or molecules, but they also allow downloads of the database components, sometimes, of the database itself.
In this conference we will present an overview on some applications of ML techniques in construction of classification and/or prediction models of biological activity, identification of mechanism of action of molecules active in phenotypic assays and unveiling of potential new targets through pathways analysis. By carrying out a virtual screening on 1,.5M compounds, we´ll apply the results to the repurposing of marketed drugs to new therapies and match predicted drug activity to gene expression or occurrence of mutations. This last approach being of particular interest for the identification of combination of therapies in cancer.
- Genome Informatics
Session Introduction
Dr Nitin Tyagi
Vardhman mahavir medical college and safdarjung hospital, India
Title: Association of adiponectin gene(adipoq) promoter polymorphism(rs266729) with coronary artery disease
Biography:
Nitin Tyagi earned his MBBS degree from Vardhman Mahavir Medical College & Safdarjung Hospital.He is currently the 3rd year post graduate student (MD,Biochemistry)at Department of Biochemistry ,VMMC & SJH,New Delhi.He has authored 7 articles in medical journals.His interests are in cardiology, oncology and medical genetics.
Abstract:
Coronary artery disease(CAD) is one of the most common cardiovascular diseases and is a major cause of morbidity and mortality worldwide.. Various studies have been done to investigate the role of ADIPOQ gene in the risk of CAD, yet their results have been inconsistent. So, there is a need of genotype analysis of ADIPOQ gene (rs266729) for further evaluation of association between ADIPOQ gene polymorphism and CAD risk.
The aim of the present study was to evaluate the impact of (rs266729) SNP in the promoter region of the ADIPOQ gene on the occurrence of CAD.
In this case control study, the study group included 50 patients with angiographically proven CAD as case group and 50 apparently healthy age and sex matched adults as control group, for the genotype (C/G) analysis of ADIPOQ gene(rs266729) by PCR-RFLP using Hha I enzyme.
Case Group: CC 20(40%), CG 16(32%) and GG 14(28%); Control Group: CC 29(58%), CG 16(32%) and GG 5(10%). The frequency of allele C in case group was 56% and 74% in control group. The frequency of allele G in case group was 44% and 26% in control group (p=0.0001). There was statistical significance between the two groups (p=0.0001).
Adiponectin gene promoter polymorphism (rs266729) is involved in the pathogenesis of coronary artery disease.