Pharmacophore identification, docking and “in silico” screening for novel CDK1 inhibitors

Pharmacophore models of cyclin-dependent kinase-1 (CDK1) inhibitors were established by using the Catalyst/HypoGen. The best pharmacophore model, Hypo1, consists of one hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD), one hydrophobic (HY) and one ring aromatic (RA) feature. The validation results of Hypo1 through cost analysis, test set prediction, Fisher's cross method and receiver operating characteristic (ROC) study indicated that the Hypo1 was statistically valuable and reliable in identifying structural diverse CDK1 inhibitors. It is further supported by the consistent results from molecular docking studies. Finally, the Hypo1 was used to “in silico” screen the NCI and MayBridge database. The preferable hits obtained were further docked into ATP binding site of CDK1, and nine promising compounds were retrieved as novel potential CDK1 inhibitors for further studies.

Graphical abstractPharmacophore model (Hypo1) of CDK1 inhibitors was established and extensively validated. Further “in silico” screening retrieved nine compounds as potential CDK1 inhibitors.Figure optionsDownload full-size imageDownload high-quality image (148 K)Download as PowerPoint slideHighlights► We established a pharmacophore model of CDK1 inhibitors using HypoGen program. ► Pharmacophore-based virtual screening combined with docking studies were performed. ► Several potential CDK1 inhibitors with different skeleton were identified.