ArticleProceedings of the National Academy of Sciences of the United States of America2000
Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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35 citing papers in PubMed, 201 citations in OpenAlex.
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- Inducible nitric oxide synthase: Regulation, structure, and inhibition.Medicinal research reviews · 2020Review
- A novel inhibitor of inducible NOS dimerization protects against cytokine-induced rat beta cell dysfunction.British journal of pharmacology · 2018Article
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- Nitric oxide synthase and structure-based inhibitor design.Nitric oxide : biology and chemistry · 2017Review
- Disrupting the Constitutive, Homodimeric Protein-Protein Interface in CK2β Using a Biophysical Fragment-Based Approach.Journal of the American Chemical Society · 2016Article
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- Novel 2,4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase.Journal of medicinal chemistry · 2015Article
- Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain.Chemical Society reviews · 2014Review
- Dimeric switch of Hakai-truncated monomers during substrate recognition: insights from solution studies and NMR structure.The Journal of biological chemistry · 2014Article
- Oncogenic protein interfaces: small molecules, big challenges.Nature reviews. Cancer · 2014Review
- Discovery of a natural product-like iNOS inhibitor by molecular docking with potential neuroprotective effects in vivo.PloS one · 2014Article
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25 authors.
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No grant is acknowledged in the PubMed record.
Abstract
Potent and selective inhibitors of inducible nitric oxide synthase (iNOS) (EC ) were identified in an encoded combinatorial chemical library that blocked human iNOS dimerization, and thereby NO production. In a cell-based iNOS assay (A-172 astrocytoma cells) the inhibitors had low-nanomolar IC(50) values and thus were >1,000-fold more potent than the substrate-based direct iNOS inhibitors 1400W and N-methyl-l-arginine. Biochemical studies confirmed that inhibitors caused accumulation of iNOS monomers in mouse macrophage RAW 264.7 cells. High affinity (K(d) approximately 3 nM) of inhibitors for isolated iNOS monomers was confirmed by using a radioligand binding assay. Inhibitors were >1,000-fold selective for iNOS versus endothelial NOS dimerization in a cell-based assay. The crystal structure of inhibitor bound to the monomeric iNOS oxygenase domain revealed inhibitor-heme coordination and substantial perturbation of the substrate binding site and the dimerization interface, indicating that this small molecule acts by allosterically disrupting protein-protein interactions at the dimer interface. These results provide a mechanism-based approach to highly selective iNOS inhibition. Inhibitors were active in vivo, with ED(50) values of <2 mg/kg in a rat model of endotoxin-induced systemic iNOS induction. Thus, this class of dimerization inhibitors has broad therapeutic potential in iNOS-mediated pathologies.
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