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.

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Mascarenhas NM, Ghoshal N

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.

Eur J Med Chem. 2008 Dec;43(12):2807-18. Epub 2007 Oct 22.

PubMed ID

18037537 [ View in PubMed

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Abstract

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 (r(2)=0.867, q(2)=0.887) with good external set prediction (r(pred)(2)=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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
N-(5-Cyclopropyl-1h-Pyrazol-3-Yl)Benzamide	Cyclin-dependent kinase 2	IC 50 (nM)	290	N/A	N/A	Details