title: 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.
abstract: 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 of a consecutive computational protocol involving homology modeling, docking experiments, and molecular dynamics simulations, we examine the characteristic structural and dynamic properties that distinguish CDK4 from CDK2 in its complexation with selective inhibitors. The results for all three CDK4-selective inhibitors under investigation show that the large-amplitude motion of a disordered loop of CDK4 is damped out in the presence of the inhibitors whereas their binding in the CDK2 active site has little effect on the loop flexibility. It is also found that the binding preference of CDK4- selective inhibitors for CDK4 over CDK2 stems from the reduced solvent accessibility in the active site of the former due to the formation of a stable hydrogen-bond triad by the Asp99, Arg101, and Thr102 side chains at the top of the active-site gorge. Besides the differences in loop flexibility and solvent accessibility, the dynamic stabilities of the hydrogen bonds between the inhibitors and the side chain of the lysine residue at the bottom of the active site also correlate well with the relative binding affinities of the inhibitors for the two CDKs. These results highlight the usefulness of this computational approach in evaluating the selectivity of a CDK inhibitor, and demonstrate the necessity of considering protein flexibility and solvent effects in designing new selective CDK4-selective inhibitors.
authors.affiliation: School of Chemistry and Molecular Engineering, Seoul National University, Seoul 151-747, Korea. hwangseo@snu.ac.kr
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.forename: Min Sun
authors.initials: MS
authors.lastname: Yeom
authors.forename: Sangyoub
authors.initials: S
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D019925:Cyclin A / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D056741:Cyclin D; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011728:Pyridones / Q000378:metabolism / Q000494:pharmacology; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D012997:Solvents
chemical_list: D019925:Cyclin A; D056741:Cyclin D; D016213:Cyclins; D004791:Enzyme Inhibitors; C429523:PD 0183812; D011518:Proto-Oncogene Proteins; D011728:Pyridones; D011743:Pyrimidines; D012997:Solvents; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases