title: 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 ( [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.
authors.affiliation: Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India.
authors.forename: A K
authors.initials: AK
authors.lastname: Saxena
authors.forename: S
authors.initials: S
authors.lastname: Saxena
authors.forename: S S
authors.initials: SS
authors.lastname: Chaudhaery
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D012984:Software
chemical_list: D000596:Amino Acids; D018841:HSP90 Heat-Shock Proteins