title: Binding site identification and role of permanent water molecule of PIM-3 kinase: A molecular dynamics study.
abstract: The kinome is a protein kinase complement of the human genome, categorized as serine/threonine and tyrosine kinases. These kinases catalyze phosphorylation reaction by using ATP as phosphoryl donor. Proviral Integration Site for Moloney Murine Leukemia Virus (PIM) kinase encodes serine/threonine protein kinases that recognized as proto-oncogene, responsible for rapid growth of cancerous cells. It is implicated in cell survival and function via cell cycle progression and its metabolism. PIM-3, sub-member of PIM kinases is a proto-oncogene, its overexpression inhibits apoptosis, and results in progression of hepatocellular carcinoma. PIM-3 is considered as a promising drug target but attempts to develop its specific inhibitors is slowed down due to the lack of 3D structure by any experimental technique. In silico techniques generally facilitate scientist to explore hidden structural features in order to improve drug discovery. In the present study, homology modeling, molecular docking and MD simulation techniques were utilized to explore the structure and dynamics of PIM-3 kinase. Induction of water molecules during molecular docking simulation explored differences in the hinge region between PIM-1 and PIM-3 kinases that may be responsible for specificity. Furthermore, role of water molecules in the active site was also explored via radial distribution function (RDF) after a 10 ns molecular dynamics (MD) simulations. Generated RDF plots exhibited the importance of water for inhibitor binding through their bridging capability that links the ligand with binding site residues.
authors.affiliation: Dr Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan. Electronic address: zaheer.qasmi@iccs.edu.
authors.forename: Zaheer
authors.initials: Z
authors.lastname: Ul-Haq
authors.affiliation: Dr Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Sana
authors.initials: S
authors.lastname: Gul
authors.affiliation: Dr Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Saman
authors.initials: S
authors.lastname: Usmani
authors.affiliation: Department of Biochemistry, Abdul Wali Khan University, Mardan 23200, Pakistan.
authors.forename: Abdul
authors.initials: A
authors.lastname: Wadood
authors.affiliation: Jamil-ur-Rahman Center for Genome Research, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Waqasuddin
authors.initials: W
authors.lastname: Khan
mesh_terms: D020134:Catalytic Domain; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D014867:Water; C499249:PIM3 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: AMBER; AutoDock; Homology modeling; MODELLER software; PIM 3 kinase; Ramachandran plot,