title: Exploring the selectivity of a ligand complex with CDK2/CDK1: a molecular dynamics simulation approach.
abstract: Cyclin-dependent kinases (CDKs) are core components of the cell cycle machinery that govern the transition between phases during cell cycle progression. Abnormalities in CDKs activity and regulation are common features of cancer, making CDK family members attractive targets for the development of anticancer drugs. Their inhibitors have entered in clinical trials to treat cancer. Very recently, Heathcote et al. (J. Med. Chem. 2010, 53:8508-8522) have found a ligand BS194 that has a high affinity with CDK2 (IC(50) = 3 nM) but shows low affinity with CDK1 (IC(50) = 30 nM). To understand the selectivity, we used homology modeling, molecular docking, molecular dynamics, and free-energy calculation to analyze the interactions. A rational three-dimensional model of the CDK1/BS194 complex is built. We found that Leu83 is a key residue that recognizes BS194 more effectively with CDK2 with good binding free energies rather than CDK1. Energetic analysis reveals that van der Waals interaction and non-polar contributions to solvent are favorable in the formation of complexes and amine group of the ligand, which plays a crucial role for binding selectivity between CDK2 and CDK1.
authors.affiliation: Computer-Aided Drug Designing and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi-, 630 003 Tamil Nadu, India.
authors.forename: Sunil Kumar
authors.initials: SK
authors.lastname: Tripathi
authors.forename: Sanjeev Kumar
authors.initials: SK
authors.lastname: Singh
authors.forename: Poonam
authors.initials: P
authors.lastname: Singh
authors.forename: Palanisamy
authors.initials: P
authors.lastname: Chellaperumal
authors.forename: Karnati Konda
authors.initials: KK
authors.lastname: Reddy
authors.forename: Chandrabose
authors.initials: C
authors.lastname: Selvaraj
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D002453:Cell Cycle; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D007930:Leucine / Q000737:chemistry; D008024:Ligands; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D013816:Thermodynamics; D014407:Tumor Cells, Cultured
chemical_list: C555217:3-(7-(benzylamino)-3-isopropylpyrazolo(1,5-a)pyrimidin-5-ylamino)-1,2,4-butanetriol; D000970:Antineoplastic Agents; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D016203:CDC2 Protein Kinase; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D007930:Leucine