Study of a ligand complexed with Cdk2/Cdk4 by computer simulation
Cyclin-dependent kinases (Cdks) play important roles in the regulation of the cell cycle. Their inhibitors have entered clinical trials to treat cancer. Very recently, Davis et al. (Nat Struct Biol 9:745-749, 2002) have found a ligand NU6102, which has a high affinity with cyclin-dependent kinase 2(Ki=6 nM) but a low affinity with cyclin-dependent kinase 4 (Ki~ 1,600 nM). To understand the selectivity, we use homology modeling, molecular docking, molecular dynamics and free-energy calculations to analyze the interactions. A rational 3D model of the Cdk4-NU6102 complex is built. Asp86 is a key residue that recognizes NU6102 more effectively with Cdk2 rather than Cdk4. Good binding free energies are obtained. Energetic analysis reveals that van der Waals interaction and nonpolar contributions to solvent are favorable in the formation of complexes and the sulfonamide group of the ligand plays a crucial role for binding selectivity between Cdk2 and Cdk4.
Homology modeling·Molecular docking·Molecular dynamics·MM-PBSA·Binding selectivity
Yongjun Jiang Jiaimei Zou Chunshan Gui
Key Laboratory for Molecular Design and Nutrition Engineering,Ningbo Institute of Technology,Zhejian Center for Drug Discovery and Design,Shanghai Institute of Materia Medica,200031, P.R. China
国际会议
杭州
英文
1385-1391
2007-04-01（万方平台首次上网日期，不代表论文的发表时间）