Pharmacophore based virtual screening, molecular docking studies to design potent heat shock protein 90 inhibitors

The identification of important chemical features of Heat Shock Protein 90 (HSP90) inhibitors will be helpful to discover the potent candidate to inhibit the HSP90 activity. The best hypothesis from Hip-Hop, Hypo1, one hydrogen bond donor (HBD), two hydrogen bond acceptors (HBA), and two hydrophobic (H) and structure-based hypothesis, SB_Hypo1, one HBA, one HBD and four H features, were generated using Discovery Studio and LigandScout, respectively. Test and decoy sets were used to corroborate the best hypotheses and the validated hypotheses were used to screen the chemical databases. Subsequently, the screened compounds were filtered by applying the rule of five, ADMET and molecular docking. Finally, four compounds were obtained as novel leads to inhibit the HSP90 activity.

Graphical abstractStructure-based, Hip-Hop hypotheses are generated and the validated hypotheses are used to screen databases and the screened compounds are sorted by applying drug-likeness and docking was carried out.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Five structure-based pharmacophore and Hip-Hop models were developed. ► Dynamic structure-based pharmacophore model was developed by removing the repeated features. ► Comparing Hip-Hop and dynamics model to find critical features of HSP90 inhibitors. ► The hypotheses were validated by test and decoy sets and used for virtual screening. ► Docking was used to sort out the hit leads from virtual screening.