4imw Citations

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

J. Med. Chem. 56 3024-32 (2013)
Related entries: 4ims, 4imx, 4imt, 4imu

Cited: 14 times
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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.

Reviews citing this publication (4)

  1. 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)
  2. 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)
  3. 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)
  4. 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)

Articles citing this publication (10)

  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. 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)
  3. 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)
  4. 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)
  5. 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)
  6. 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)
  7. 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)
  8. 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)
  9. 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)
  10. The "Sticky Patch" Model of Crystallization and Modification of Proteins for Enhanced Crystallizability. Derewenda ZS, Godzik A. Methods Mol. Biol. 1607 77-115 (2017)