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

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 ( [image omitted] = 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.