Pharmacophore-based virtual screening and docking studies on Hsp90 inhibitors

Abstract

Hsp90 (Heat shock protein 90) is an important therapeutic target for the treatment of cancer. To identify important chemical features for Hsp90 inhibitory activity, a 3D-QSAR pharmacophore model was developed using a set of 61 inhibitors (a training set of 31 and a test set of 30 compounds) belonging to a series of 2-amino-6-halopurine and 7'-substituted benzothiazolothio- and pyridinothiazolothio-purines. The best HypoGen model consisted of five pharmacophoric features: one hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD) and three hydrophobic (HY) groups. It showed a high correlation coefficient (r = 0.943) and low root mean square deviation (RMSD = 0.751). This model was validated against 30 known Hsp90 inhibitors, where it showed a high predictive value for R(2)pred = 0.805], thus confirming that HY, HBA and HBD features are essential for Hsp90 inhibition. The validated pharmacophore model (Hypo-1) was used as a 3D query for virtual screening to retrieve potential inhibitors from the Maybridge and National Cancer Institute (NCI) databases. The hit compounds were subsequently subjected to molecular docking studies and, finally, five hits were prioritized as potential leads based on GoldScore function.

Synthesis and Pharmacophore Modelling of 2,6,9-Trisubstituted Purine Derivatives and Their Potential Role as Apoptosis-Inducing Agents in Cancer Cell Lines

“…In fact, many other factors need to be considered in the relationship of structural pattern and cytotoxicity activity. Therefore, it is necessary to search for other tools to understand the antitumor activity in silico and to explore the structural requirements determining the observed biological properties [ 31 , 32 ].…”

Integration of pharmacophore mapping and molecular docking in sequential virtual screening: towards the discovery of novel JAK2 inhibitors

“…[11][12][13][14] Recently, a combined screening strategy of pharmacophore mapping and molecular docking show synergetic effect in virtual screening. 15,16 As such, the integrally globally and partially essential pharmacophoric features for both of ligand and receptor can be simultaneously characterized, thereby showing more preferable performance (e.g. efficiency and accuracy) than the individually used method.…”

Exploration of structural and physicochemical requirements and search of virtual hits for aminopeptidase N inhibitors

“…Multiple pharmacophore screening and its validation Pharmacophore models (both ligand-and structure-based) are used for the screening of databases containing large number of diverse molecules to find compounds that could be proposed as potential virtual hits [39][40][41][42][43][44][45][46]. An ideal pharmacophore query is able to capture active molecules selectively from the databases discarding inactive molecules.…”