title: Drug design for protein kinases and phosphatases: flexible-receptor docking, binding affinity and specificity, and drug-binding kinetics.
abstract: This article reviews some of our experiences on applying computational techniques to aid the design of drugs targeting protein kinases and phosphatases. It is not a comprehensive review. Rather, it focuses on several less explored approaches or ideas that we have experiences on. It reviews some recent improvements on the Poisson-Boltzmann/Surface Area model for calculating binding affinity and discusses ways to perform calculations that are more tolerant to statistical and systematic errors. Several new ways to incorporate protein flexibility in molecular docking and estimating binding affinity are also discussed. Its discussions also go beyond binding affinity to considering drug-binding kinetics, not only on investigating protein-ligand interactions in isolation, but also on accounting for upstream and downstream influences that can occur in cells, through kinetic modeling of cell signaling. This review also describes a quick molecular simulation method for understanding drug-binding kinetics at the molecular level, with the hope of generating guiding principles for designing drugs with the desired kinetic properties. Sources of drug-binding selectivity that appear obvious but often overlooked are also discussed.
authors.affiliation: Department of Chemistry and Biochemistry and Center for Nanoscience, University of Missouri-Saint Louis, One University Boulevard, St. Louis, Missouri 63121, USA. wongch@umsl.edu
authors.forename: Chung F
authors.initials: CF
authors.lastname: Wong
authors.forename: Sneha
authors.initials: S
authors.lastname: Bairy
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D007700:Kinetics; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000187:drug effects*; D016012:Poisson Distribution; D011494:Protein Kinases / Q000737:chemistry / Q000187:drug effects*
chemical_list: D004364:Pharmaceutical Preparations; D011494:Protein Kinases; D010749:Phosphoprotein Phosphatases