An efficient tool for identifying inhibitors based on 3D-QSAR and docking using feature-shape pharmacophore of biologically active conformation – A case study with CDK2/CyclinA

This study proposes a fast and efficient approach for identifying novel inhibitors when the biologically active conformation of an inhibitor is known. The present study was carried out with CDK2/CyclinA inhibitors. The co-crystal structure of the most active ligand with CDK2/CyclinA was converted into a feature-shape query. This query served three purposes (i) alignment of molecules to generate 3D-QSAR model, (ii) rigid docking to the active site using GOLD, (iii) extracting hits from databases. A statistically valid 3D-QSAR (r2 = 0.867, q2 = 0.887) with good external set prediction (rpred2 = 0.890) was obtained. The docked poses were analyzed based on their interaction with hinge region (Glu81–Leu83) of CDK2. A reasonably good consensus score was generated using 11 scoring functions. The developed model was then successfully used to identify potential leads for CDK2/CyclinA inhibitors.

Graphical abstractThis study proposes a fast and efficient approach for VS when the biologically active conformation of an inhibitor is known. The present study was carried out with CDK2/CyclinA inhibitors.Figure optionsDownload full-size imageDownload as PowerPoint slide