title: Docking and 3D-QSAR modeling of cyclin-dependent kinase 5/p25 inhibitors.
abstract: Structure-based 3D-QSAR approaches (CoMFA and CoMSIA) were applied to understand the structural requirements of the Cyclin-dependent kinase 5/p25 inhibitors. Cyclin-dependent kinase 5 (CDK5) is believed to play an important role in the development of the central nervous system during the process of mammalian embryogenesis. Genetic algorithm based docking program (GOLD) was successfully utilized to orient the compounds inside the binding pocket of the CDK5/p25 structure. The adapted alignment method with the suitable parameters resulted in a reliable model. Furthermore, the final model was robust enough to forecast the activities of test compounds, satisfactorily. The contour maps were produced around the functional groups to understand the SAR requirements. Moreover, we also investigate the structural attributes of the inhibitors which make them selective toward CDK5/p25 over its close counterpart, i.e., CDK2. The study could be helpful to rationalize the new compounds with better inhibition and selectivity profiles against CDK5/p25.
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan. zaheer.qasmi@iccs.edu
authors.forename: Zaheer
authors.initials: Z
authors.lastname: Ul Haq
authors.forename: Reaz
authors.initials: R
authors.lastname: Uddin
authors.forename: Lam Kok
authors.initials: LK
authors.lastname: Wai
authors.forename: Abdul
authors.initials: A
authors.lastname: Wadood
authors.forename: Nordin Haji
authors.initials: NH
authors.lastname: Lajis
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000503:physiopathology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D021281:Quantitative Structure-Activity Relationship; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
chemical_list: D047428:Protein Kinase Inhibitors; D051360:Cyclin-Dependent Kinase 5; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2