Loop flexibility and solvent dynamics as determinants for the selective inhibition of cyclin-dependent kinase 4: comparative molecular dynamics simulation studies of CDK2 and CDK4.

摘要: The design and discovery of selective cyclin-dependent kinase 4 (CDK4) inhibitors have been actively pursued in order to develop therapeutic cancer treatments. By means a consecutive computational protocol involving homology modeling, docking experiments, molecular dynamics simulations, we examine the characteristic structural dynamic properties that distinguish CDK4 from CDK2 its complexation with inhibitors. results for all three CDK4-selective under investigation show large-amplitude motion disordered loop is damped out presence whereas their binding active site has little effect on flexibility. It also found preference CDK4- over stems reduced solvent accessibility former due formation stable hydrogen-bond triad by Asp99, Arg101, Thr102 side chains at top active-site gorge. Besides differences flexibility accessibility, stabilities hydrogen bonds between chain lysine residue bottom correlate well relative affinities two CDKs. These highlight usefulness this approach evaluating selectivity CDK inhibitor, demonstrate necessity considering protein effects designing new