title: A computational model of binding thermodynamics: the design of cyclin-dependent kinase 2 inhibitors.
abstract: The cyclin-dependent protein kinases are important targets in drug discovery because of their role in cell cycle regulation. In this computational study, we have applied a continuum solvent model to study the interactions between cyclin-dependent kinase 2 (CDK2) and analogues of the clinically tested anticancer agent flavopiridol. The continuum solvent model uses Coulomb's law to account for direct electrostatic interactions, solves the Poisson equation to obtain the electrostatic contributions to solvation energy, and calculates scaled solvent-accessible surface area to account for hydrophobic interactions. The computed free energy of binding gauges the strength of protein-ligand interactions. Our model was first validated through a study on the binding of a number of flavopiridol derivatives to CDK2, and its ability to identify potent inhibitors was observed. The model was then used to aid in the design of novel CDK2 inhibitors with the aid of a computational sensitivity analysis. Some of these hypothetical structures could be significantly more potent than the lead compound flavopiridol. We applied two approaches to gain insights into designing selective inhibitors. One relied on the comparative analysis of the binding pocket for several hundred protein kinases to identify the parts of a lead compound whose modifications might lead to selective compounds. The other was based on building and using homology models for energy calculations. The homology models appear to be able to classify ligand potency into groups but cannot yet give reliable quantitative results.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0365, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Sims
authors.forename: Chung F
authors.initials: CF
authors.lastname: Wong
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000737:chemistry; D042846:CDC2-CDC28 Kinases; D003205:Computing Methodologies; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005419:Flavonoids / Q000737:chemistry*; D008954:Models, Biological; D010880:Piperidines / Q000737:chemistry*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011518:Proto-Oncogene Proteins; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D010880:Piperidines; D011518:Proto-Oncogene Proteins; C077990:alvocidib; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases