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Structure-guided design of selective inhibitors of neuronal nitric oxide synthase.

Huang H, Li H, Martásek P, Roman LJ, Poulos TL, Silverman RB
J Med Chem 56 3024-32 (2013)
Related entries: 4ims, 4imt, 4imu, 4imw

Cited: 19 times
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Abstract

Nitric oxide synthases (NOSs) comprise three closely related isoforms that catalyze the oxidation of L-arginine to L-citrulline and the important second messenger nitric oxide (NO). Pharmacological selective inhibition of neuronal NOS (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. Here, we present a structure-guided, selective nNOS inhibitor design based on the crystal structure of lead compound 1 in nNOS. The best inhibitor, 7, exhibited low nanomolar inhibitory potency and good isoform selectivities (nNOS over eNOS and iNOS are 472-fold and 239-fold, respectively). Consistent with the good selectivity, 7 binds to nNOS and eNOS with different binding modes. The distinctly different binding modes of 7, driven by the critical residue Asp597 in nNOS, offers compelling insight to explain its isozyme selectivity, which should guide future drug design programs.

Articles - 4imx mentioned but not cited (1)

  1. Structure-guided design of selective inhibitors of neuronal nitric oxide synthase. Huang H, Li H, Martásek P, Roman LJ, Poulos TL, Silverman RB. J Med Chem 56 3024-3032 (2013)


Reviews citing this publication (5)

  1. Nitric oxide synthase inhibition and oxidative stress in cardiovascular diseases: possible therapeutic targets? Rochette L, Lorin J, Zeller M, Guilland JC, Lorgis L, Cottin Y, Vergely C. Pharmacol Ther 140 239-257 (2013)
  2. Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain. Mukherjee P, Cinelli MA, Kang S, Silverman RB. Chem Soc Rev 43 6814-6838 (2014)
  3. Nitric oxide synthase inhibitors: a review of patents from 2011 to the present. Yang Y, Yu T, Lian YJ, Ma R, Yang S, Cho JY. Expert Opin Ther Pat 25 49-68 (2015)
  4. The latest advances in the discovery of nitric oxide hybrid drug compounds. Serafim RAM, Pernichelle FG, Ferreira EI. Expert Opin Drug Discov 12 941-953 (2017)
  5. The "Sticky Patch" Model of Crystallization and Modification of Proteins for Enhanced Crystallizability. Derewenda ZS, Godzik A. Methods Mol Biol 1607 77-115 (2017)

Articles citing this publication (13)

  1. Potent and selective double-headed thiophene-2-carboximidamide inhibitors of neuronal nitric oxide synthase for the treatment of melanoma. Huang H, Li H, Yang S, Chreifi G, Martásek P, Roman LJ, Meyskens FL, Poulos TL, Silverman RB. J Med Chem 57 686-700 (2014)
  2. 2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity. Kang S, Li H, Tang W, Martásek P, Roman LJ, Poulos TL, Silverman RB. J Med Chem 58 5548-5560 (2015)
  3. Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors. Cinelli MA, Li H, Chreifi G, Poulos TL, Silverman RB. J Med Chem 60 3958-3978 (2017)
  4. Novel 2,4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase. Mukherjee P, Li H, Sevrioukova I, Chreifi G, Martásek P, Roman LJ, Poulos TL, Silverman RB. J Med Chem 58 1067-1088 (2015)
  5. Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus. Holden JK, Kang S, Beasley FC, Cinelli MA, Li H, Roy SG, Dejam D, Edinger AL, Nizet V, Silverman RB, Poulos TL. Chem Biol 22 785-792 (2015)
  6. Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase. Cinelli MA, Li H, Pensa AV, Kang S, Roman LJ, Martásek P, Poulos TL, Silverman RB. J Med Chem 58 8694-8712 (2015)
  7. Structure-based design of bacterial nitric oxide synthase inhibitors. Holden JK, Kang S, Hollingsworth SA, Li H, Lim N, Chen S, Huang H, Xue F, Tang W, Silverman RB, Poulos TL. J Med Chem 58 994-1004 (2015)
  8. Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker. Wang HY, Qin Y, Li H, Roman LJ, Martásek P, Poulos TL, Silverman RB. J Med Chem 59 4913-4925 (2016)
  9. Structure-Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens. Wesseling CMJ, Slingerland CJ, Veraar S, Lok S, Martin NI. ACS Infect Dis 7 3314-3335 (2021)
  10. Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors. Jing Q, Li H, Chreifi G, Roman LJ, Martásek P, Poulos TL, Silverman RB. Bioorg Med Chem Lett 23 5674-5679 (2013)
  11. Microwave-assisted protection of primary amines as 2,5-dimethylpyrroles and their orthogonal deprotection. Walia A, Kang S, Silverman RB. J Org Chem 78 10931-10937 (2013)
  12. First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate. Cinelli MA, Reidl CT, Li H, Chreifi G, Poulos TL, Silverman RB. J Med Chem 63 4528-4554 (2020)
  13. Inhibitor Bound Crystal Structures of Bacterial Nitric Oxide Synthase. Holden JK, Dejam D, Lewis MC, Huang H, Kang S, Jing Q, Xue F, Silverman RB, Poulos TL. Biochemistry 54 4075-4082 (2015)


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