Biophysical Society Thematic Meeting

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

(

) 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.