Biophysical Society Thematic Meeting - November 16-20, 2015

Biophysics in the Understanding, Diagnosis, and Treatment of Infectious Diseases Poster Abstracts

36-POS Board 36 Towards Discovering Novel Drug Target Sites and Small Compound Inhibitors of Heat Shock Protein 90 (Hsp90): A Structural Bioinformatics Approach David L. Penkler , Ozlem Tastan Bishop. Rhodes University, Grahamstown, South Africa. Hsp90 is a molecular chaperone heavily implicated in maintaining cellular homeostasis, ensuring the correct folding, stabilization and activation of a host of different client proteins, many of which are involved in important biological processes. In diseases such as cancer and malaria, infected cells undergo a vast barrage of environmental insults such as, hypoxia, temperature and pH variation, and oxidative outbursts, which in most cases would arrest the normal function and progression of the cell, an outcome largely avoided through cellular rescue by Hsp90. Given its importance it is thus not surprising that Hsp90 has gathered much attention as a potential drug target. To date the vast majority of known Hsp90 inhibitors include small molecules which actively compete for the ATP binding site located on the N-terminal of the protein. The objective of this study was to investigate natural compounds as potential inhibitors that putatively target functional sites on Hsp90 other than the ATP binding pocket. Whole protein in silico molecular docking experiments were performed using 574 natural compounds from the SANCDB (www.sancdb.rubi.ru.ac.za) against both human and Plasmodium falciparum cytosolic orthologs. Subsequent clustering analysis revealed several strong lead candidate compounds specific to putative Hsp90-Hop interaction sites on human and parasite models. Further in silico sequence and structural analysis of these bound target sites revealed two distinct binding pockets in close proximity to specific Hop interacting residues located in the middle domain of both organisms. In depth molecular dynamics simulations were done to validate the suitability of 20 re-docked lead compound hits for use as putative Hsp90 inhibitors. Here we present the discovery of several South African natural compounds as potential inhibitors, specific to binding pockets involved in Hop-Hsp90 binding.

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