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Peripheral but crucial: a hydrophobic pocket (Tyr(706), Leu(337), and Met(336)) for potent and selective inhibition of neuronal nitric oxide synthase.

ABSTRACT: Selective inhibition of the neuronal isoform of nitric oxide synthase (nNOS) over endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) has become a promising strategy for the discovery of new therapeutic agents for neurodegenerative diseases. However, because of the high sequence homology of different isozymes in the substrate binding pocket, developing inhibitors with both potency and excellent isoform selectivity remains a challenging problem. Herein, we report the evaluation of a recently discovered peripheral hydrophobic pocket (Tyr(706), Leu(337), and Met(336)) that opens up upon inhibitor binding and its potential in designing potent and selective nNOS inhibitors using three compounds, 2a, 2b, and 3. Crystal structure results show that inhibitors 2a and 3 adopted the same binding mode as lead compound 1. We also found that hydrophobic interactions between the 4-methyl group of the aminopyridine ring of these compounds with the side chain of Met(336), as well as the ?-? stacking interaction between the pyridinyl motif and the side chain of Tyr(706) are important for the high potency and selectivity of these nNOS inhibitors.

SUBMITTER: Xue F

PROVIDER: S-EPMC2952696 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Peripheral but crucial: a hydrophobic pocket (Tyr(706), Leu(337), and Met(336)) for potent and selective inhibition of neuronal nitric oxide synthase.

Xue Fengtian F Li Huiying H Fang Jianguo J Roman Linda J LJ Martásek Pavel P Poulos Thomas L TL Silverman Richard B RB

Bioorganic & medicinal chemistry letters 20100826 21

Selective inhibition of the neuronal isoform of nitric oxide synthase (nNOS) over endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) has become a promising strategy for the discovery of new therapeutic agents for neurodegenerative diseases. However, because of the high sequence homology of different isozymes in the substrate binding pocket, developing inhibitors with both potency and excellent isoform selectivity remains a challenging problem. Herein, we report t ...[more]

PMID: 20833542

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Project description:The EFSA Panel on Food Additives and Flavourings (FAF) provides a scientific opinion on tartaric acid-tartrates (E 334-337, 354) when used as food additives. The Scientific Committee for Food (SCF) in 1990 established an acceptable daily intake (ADI) of 30 mg/kg body weight (bw) per day, for l(+)-tartaric acid and its potassium and sodium salts. The metabolism of l(+)-tartaric acid and its potassium sodium salt was shown to be species dependent, with a greater absorption in rats than in humans. No toxic effects, including nephrotoxicity, were observed in toxicological studies in which the l(+)-form was tested. There was no indication for a genotoxic potential of tartaric acid and its sodium and potassium salts. In a chronic study in rats, no indication for carcinogenicity of monosodium l(+)-tartrate was reported at the highest dose tested (3,100 mg/kg bw per day). The available studies for maternal or developmental toxicity did not report any relevant effects; no studies for reproductive toxicity were available; however, no effects on reproductive organs were observed in the chronic toxicity study. The Panel concluded that the data on systemic availability were robust enough to derive a chemical-specific uncertainty factor instead of the usual default uncertainty factor of 100. A total uncertainty factor of 10 was derived by applying a total interspecies uncertainty factor of 1 instead of 10, based on data showing lower internal exposure in humans compared to rats. The Panel established a group ADI for l(+)-tartaric acid-tartrates (E 334-337 and E 354) of 240 mg/kg bw per day, expressed as tartaric acid, by applying the total uncertainty factor of 10 to the reference point of 3,100 mg sodium tartrate/kg bw per day, approximately to 2,440 mg tartaric acid/kg bw per day. The exposure estimates for the different population groups for the refined non-brand-loyal exposure scenario did not exceed the group ADI of 240 mg/kg bw per day, expressed as tartaric acid. Some recommendations were made by the Panel.

Dataset Information

Peripheral but crucial: a hydrophobic pocket (Tyr(706), Leu(337), and Met(336)) for potent and selective inhibition of neuronal nitric oxide synthase.

Publications

Peripheral but crucial: a hydrophobic pocket (Tyr(706), Leu(337), and Met(336)) for potent and selective inhibition of neuronal nitric oxide synthase.

Similar Datasets

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