Implications for isoform-selective inhibitor design derived from the binding mode of bulky isothioureas to the heme domain of endothelial nitric-oxide synthase

The Journal of Biological Chemistry
C S RamanThomas L Poulos

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

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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
Mar 14, 2007·Journal of Molecular Graphics & Modelling·V AparnaB Gopalakrishnan
Apr 28, 2009·Bioorganic & Medicinal Chemistry Letters·Guo Hua JinRaok Jeon
May 30, 2003·Journal of Medicinal Chemistry·Qiang JiaPeng G Wang

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