Poster abstracts

Poster number 8 submitted by In-Hee Park

Novel Ligand-Induced-Fit Simulation of Survivin Via Replica Exchange Molecular Dynamics (REMD) and Receptor-Based Reverse Virtual Screening (VS)

In-Hee Park (Chemical Physics Program, The Ohio State University, Columbus, OH), Chenglong Li (Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH)

Abstract:
Survivin is an anti-cancer drug target due to its over-expression in cancer cells. It has two important binding hot spots - the BIR domain and its dimerization interface. In this study, we probe conformational ‘plasticity’ in the dimerization interface aiming at design and discovery of dimerization inhibitors. The Abbott laboratory has identified a small molecule binding site near the interface of the survivin dimer through NMR screening experiments. A benchmarking of the Abbott8 compound binding mode aided in the refinement of the receptor conformation by exploring the survivin conformational flexibility. The REMD method was utilized to enhance the sampling of the dimer; and a ‘reverse VS ’ with Abbott8 compound against a large set of conformations sampled via REMD allowed for a reproduction of the NMR experimental binding mode. Compared to the X-ray structure, a prolific conformational change in the “switch loop” connecting the BIR domain and C-term helix provides a suitable ligand binding pocket, whose functional importance was recently identified via the determination of a survivin-borealin-INCENP core structure of the chromosomal passenger complex (CPC).

Keywords: Survivin, Replica Exchange Molecular Dynamics, Virtual Screening