Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 43, Issue 12, Pages 2807-2818Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2007.10.016
Keywords
Biologically active conformation; CDK2/CyclinA inhibitors; 3D-QSAR; Docking; Pharmacophore; Virtual screening
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Funding
- Mission Mode Program of CSIR
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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. (C) 2007 Elsevier Masson SAS. All fights reserved.
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