Molecular modelling and docking studies on heat shock protein 90 (Hsp90) inhibitors

Abstract

An adenosine tri-phosphate (ATP)-dependent molecular chaperone heat shock protein (Hsp90) is of current interest as a potential anticancer drug target. It has several oncogenic client proteins involved in signal transduction, cell cycle regulation and apoptosis. In order to identify essential chemical functional features for Hsp90 inhibition, a pharmacophore model consisting of one hydrogen bond donor, two hydrogen bond acceptor lipid and one hydrophobic feature has been developed using Hypogen (Catalyst 2.0 software) on a total set of 103 inhibitors consisting of 16 and 87 compounds in the training and the test set, respectively. The model shows good correlation for the training (r ²= 0.887) and the test set ( = 0.692). In view of the X-ray data structure of Hsp90, GOLD 3.2 docking software was used to dock the 16 training set compounds. A good correlation (r ²= 0.699) was observed between the experimental biological activity and the top-ranked Goldscore. The analysis of conserved patterns across the Hsp90 family, using the human Hsp90 X-ray structure as an alignment template, led to the identification of important amino acids involved in the ligand-binding interactions, which were found to be similar to those observed in docking studies. Hence, the best-generated pharmacophore model can be used for designing new Hsp90 inhibitors.

Keywords:

• Hypogen
• Hsp90
• GOLD
• conserved
• pharmacophore

Acknowledgements

The authors are thankful for financial assistance by the Ministry of Health (SS), the Council of Scientific and Industrial Research (SSC), and the Department of Science and Technology for travel to present this work (AKS) and to Mr. A.S. Kushwaha for technical assistance.