Abstract
Nitric oxide produced by nitric-oxide synthase (NOS) is not only involved in a wide range of physiological functions but also in a variety of pathological conditions. Isoform-selective NOS inhibitors are highly desirable to regulate the NO production of one isoform beneficial to normal physiological functions from the uncontrolled NO production of another isoform that accompanies certain pathological states. Crystal structures of the heme domain of the three NOS isoforms have revealed a very high degree of similarity in the immediate vicinity of the heme active site illustrating the challenge of isoform-selective inhibitor design. Isothioureas are potent NOS inhibitors, and the structures of the endothelial NOS heme domain complexed with isothioureas bearing small S-alkyl substituents have been determined (Li, H., Raman, C.S., Martásek, P., Král, V., Masters, B.S.S., and Poulos, T.L. (2000) J. Inorg. Biochem. 81, 133--139). In the present communication, the binding mode of larger bisisothioureas complexed to the endothelial NOS heme domain has been determined. These structures afford a structural rationale for the known inhibitory activities. In addition, these structures provide clues on how to exploit the longer inhibitor sub...Continue Reading
References
Aug 1, 1992·The Journal of Experimental Medicine·H J ChoC Nathan
Dec 1, 1990·Acta Physiologica Scandinavica·M G PerssonP Hedqvist
Jul 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·R G KnowlesS Moncada
Oct 31, 1989·Biochemical and Biophysical Research Communications·B MayerE Böhme
Jan 1, 1985·Methods in Enzymology·T A Jones
Oct 27, 1995·Journal of Medicinal Chemistry·J F KerwinP L Feldman
Jan 1, 1995·Annual Review of Physiology·O W Griffith, D J Stuehr
Nov 1, 1995·Journal of Biomolecular NMR·F DelaglioA Bax
Feb 15, 1996·Biochemical and Biophysical Research Communications·P MartasekB S Masters
Feb 23, 1996·Biochemical Pharmacology·G J Southan, C Szabó
Apr 1, 1996·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·B S MastersP Martasek
Jul 1, 1996·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Z G ZhangM Chopp
Jun 6, 1997·Journal of Medicinal Chemistry·B G ShearerE S Furfine
Apr 16, 1998·Science·B R CraneJ A Tainer
Jun 5, 1998·The Journal of Biological Chemistry·N BecR Lange
Jul 21, 1998·Journal of Medicinal Chemistry·J L CollinsE S Furfine
Aug 28, 1998·Naunyn-Schmiedeberg's Archives of Pharmacology·B Mayer, P Andrew
Sep 16, 1998·Current Opinion in Chemical Biology·B R Babu, O W Griffith
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
Jan 6, 1999·Cell·C S RamanT L Poulos
Mar 13, 1999·Nature Structural Biology·T O FischmannP C Weber
May 13, 1999·Biochimica Et Biophysica Acta·D J Stuehr
Jul 20, 1999·The Journal of Biological Chemistry·H LiT L Poulos
Aug 17, 1999·Journal of Medicinal Chemistry·H HuangR B Silverman
Aug 28, 1999·The Journal of Biological Chemistry·B R BabuO W Griffith
Sep 15, 1999·Proceedings of the National Academy of Sciences of the United States of America·P E ChabrierS Moncada
Jan 8, 2000·Biochemistry·A R HurshmanM A Marletta
Aug 6, 2000·Free Radical Biology & Medicine·D W ReifJ E Macdonald
Oct 29, 2000·Journal of Inorganic Biochemistry·H LiT L Poulos
Jan 1, 1997·Methods in Enzymology·Zbyszek Otwinowski, Wladek Minor
Citations
Dec 4, 2002·Nature Reviews. Drug Discovery·Patrick Vallance, James Leiper
Apr 9, 2004·Proceedings of the National Academy of Sciences of the United States of America·Roman FedorovIlme Schlichting
Sep 8, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Carla I NietoDarío Acuña-Castroviejo
Jul 27, 2012·Bioorganic & Medicinal Chemistry·Elodie LohouValérie Collot
Dec 15, 2010·Biochimica Et Biophysica Acta·Changjian FengGordon Tollin
Mar 14, 2007·Journal of Molecular Graphics & Modelling·V AparnaB Gopalakrishnan
Aug 13, 2004·The EMBO Journal·Aaron A Thompson, Olve B Peersen
Jan 15, 2005·Proteins·Stewart B KirtonRichard D Taylor
Apr 28, 2009·Bioorganic & Medicinal Chemistry Letters·Guo Hua JinRaok Jeon
Sep 5, 2003·The Journal of Biological Chemistry·Roman FedorovIlme Schlichting
Dec 12, 2003·Journal of Medicinal Chemistry·Haitao JiRichard B Silverman
May 1, 2007·Bioorganic & Medicinal Chemistry Letters·Yoon Jung KimRaok Jeon
May 30, 2003·Journal of Medicinal Chemistry·Qiang JiaPeng G Wang
Jul 22, 2005·Journal of Medicinal Chemistry·Hans MatterHarald H H W Schmidt
Jun 12, 2002·Biochemistry·Antonius C F GorrenBernd Mayer