Download MendeleyStructure-guided design of selective inhibitors of neuronal nitric oxide synthase.
Huang, H., Li, H., Martasek, P., Roman, L.J., Poulos, T.L., Silverman, R.B.(2013) J Med Chem 56: 3024-3032
- PubMed: 23451760
- DOI: https://doi.org/10.1021/jm4000984
- Primary Citation of Related Structures:
4IMS, 4IMT, 4IMU, 4IMW, 4IMX - PubMed 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.
Organizational Affiliation:
Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.
