Selective ATP competitive leads of CDK4: Discovery by 3D-QSAR pharmacophore mapping and molecular docking approach

Abstract

The discovery of ATP competitive CDK4 inhibitors is an on-going challenging task in cancer therapy. Here, an attempt has been made to develop new leads targeting ATP binding site of CDK4 by applying 3D-QSAR pharmacophore mapping and molecular docking methods The outcome of 6 leads offers a significant contribution for selective CDK4 inhibition, since they show potential binding interactions with Val⁹⁶, Arg¹⁰¹, and Glu¹⁴⁴ residues of CDK4, that are unique and from other kinases. It is worth noting that there is a striking similarity in binding interactions of the leads and known CDK4 inhibitors, namely Abemaciclib, Palbociclib and Ribociclib. Further key features, including high dock score value, good predicted activity, scaffold diversity, and the acceptable ADME profile of leads, provide a great opportunity for the development of highly potent and selective ATP competitive inhibitors of CDK4.

Keywords: 3D-QSAR pharmacophore; ADME; ATP competitive inhibitors; CDK4; Docking; Virtual screening.