Crystal structures of constitutive nitric oxide synthases in complex with de novo designed inhibitors.
New nitric oxide synthase (NOS) inhibitors were designed de novo with knowledge gathered from the studies on the nNOS-selective dipeptide inhibitors. Each of the new inhibitors consists of three fragments: an aminopyridine ring, a pyrrolidine, and a tail of various length and polarity. The in vitro inhibitory assays indicate good potency and isoform selectivity for some of the compounds. Crystal structures of these inhibitors bound to either wild type or mutant nNOS and eNOS have confirmed design expectations. The aminopyridine ring mimics the guanidinium group of L-arginine and functions as an anchor to place the compound in the NOS active site where it hydrogen bonds to a conserved Glu. The rigidity of the pyrrolidine ring places the pyrrolidine ring nitrogen between the same conserved Glu and the selective residue nNOS Asp597/eNOS Asn368, which results in similar interactions observed with the alpha-amino group of dipeptide inhibitors bound to nNOS. These structures provide additional information to help in the design of inhibitors with greater potency, physicochemical properties, and isoform selectivity.
Igarashi
Jotaro
J
Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, California 92697-3900, USA.
Li
Huiying
H
Jamal
Joumana
J
Ji
Haitao
H
Fang
Jianguo
J
Lawton
Graham R
GR
Silverman
Richard B
RB
Poulos
Thomas L
TL
D000631:Aminopyridines / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D009154:Mutation; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D011759:Pyrrolidines / Q000737:chemistry*; D013816:Thermodynamics
D000631:Aminopyridines; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011759:Pyrrolidines; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III