title: Electrostatic Control of Isoform Selective Inhibitor Binding in Nitric Oxide Synthase.
abstract: Development of potent and isoform selective nitric oxide synthase (NOS) inhibitors is challenging because of the structural similarity in the heme active sites. One amino acid difference between NOS isoforms, Asp597 in rat neuronal NOS (nNOS) versus Asn368 in bovine endothelial NOS (eNOS), has been identified as the structural basis for why some dipeptide amide inhibitors bind more tightly to nNOS than to eNOS. We now have found that the same amino acid variation is responsible for substantially different binding modes and affinity for a new class of aminopyridine-based inhibitors.
authors.affiliation: Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California , Irvine, California 92697-3900, United States.
authors.forename: Huiying
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.
authors.forename: Heng-Yen
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.
authors.forename: Soosung
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
authors.affiliation: Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California , Irvine, California 92697-3900, United States.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Poulos
mesh_terms: D000631:Aminopyridines / Q000378:metabolism*; D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002417:Cattle; D019295:Computational Biology; D004791:Enzyme Inhibitors / Q000378:metabolism*; D007527:Isoenzymes; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D055672:Static Electricity; D014961:X-Ray Diffraction
chemical_list: D000631:Aminopyridines; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D001224:Aspartic Acid; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III