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M. Elizabeth Sobhia and Ranajit Shinde
Accepted Abstracts: Drug Design
Proteins may be characterized by the presence of numerous binding sites. Active sites are the key sites of proteins, generally located in cavities that are rich in functional groups and small molecules are often attracted to these cavities for binding. Allosteric sites are specific sites present on the surface of enzymes or protein molecules to which the modulator or effector molecule bind and subsequently modify the protein activity by either activating it or inhibiting it. The use of allosteric sites as potential drug targets has gained importance ever since their discovery by means of X-ray crystallography. Protein tyrosine phosphatase 1B (PTP1B) has been identified as an attractive target for both type 2 diabetes and obesity. It has been shown to play a negative role in the insulin signaling pathways. The known active site PTP1B inhibitors lack appropriate pharmacokinetic properties and selectivity over other PTPs. In the present study we have used different in silico approaches for the design of selective and novel PTP1B allosteric inhibitors. A shape based virtual screening protocol was employed to identify potential PTP1B allosteric inhibitors. Some of the molecules have shown high percentage of inhibition in enzymatic assays. Using molecular dynamics approaches, we have also studied the flexibility of the alpha-7 helix in PTP1B and have carried out binding free energy calculations and energy decomposition analysis for the allosteric inhibitors. We have also characterized the different geometric criteria required for studying the open and closed state of WPD loops in PTP1B. The results will be discussed in the presentation.
Dr. M. Elizabeth Sobhia completed her Ph.D from Department of Crystallography and Biophysics, University of Madras. Chennai, India. She is working as an assistant professor at NIPER (National Institute of Pharmaceutical Education and Research), a Centre of excellence for advanced studies and research in Pharmaceutical Sciences. Her research interests include: Application of Computer Aided Drug Design methods in lead identification & optimization, in silico studies on ADME/T prediction, and Molecular Dynamics Simulation. Therapeutic targets of her research interests include PTP1B, CCR2, PKC-β2 ALR2, Neuraminidase and Enoyl reductase. She holds more than 50 research publications in International journals to her credit.