Screening of novel and selective inhibitors for neuronal nitric oxide synthase (nNOS) via structure-based drug design techniques

Abstract

NO, or nitric oxide, is produced by a family of enzymes called nitric oxide synthase (NOS) from L-arginine. NO regulates many physiological functions such as smooth muscle relaxation, immune defense, and memory function. The overproduction of NO by the neuronal isoform of nitric oxide synthase (nNOS) is implicated in neurodegeneration and neuropathic pain, making nNOS inhibition a promising therapeutic approach. Many developed nNOS inhibitors, generally L-arginine mimetics, have some issues in selectivity and bioavailability. According to earlier studies, targeting nNOS has the advantage of decreasing excess NO in the brain while avoiding the negative consequences of inhibiting the two isozymes: endothelial NOS (eNOS) and inducible NOS (iNOS). This study applied structure-based virtual screening, molecular docking, and molecular dynamics simulations to design potent and selective inhibitors against nNOS over related isoforms (eNOS and iNOS) using human X-ray crystal structures of the NOS isoforms. It was discovered that some compounds displayed a very good inhibitory potency for hnNOS and moderate selectivity for the other isozymes, eNOS and iNOS, in addition to good solubility and desirable physiochemical properties. The compounds which showed good stability and selectivity with nNOS, such as ZINC000013485422, can be interesting and informative guidance for designing more potent human nNOS inhibitors.

Communicated by Ramaswamy H. Sarma

Keywords:

• Nitric oxide synthase
• neurodegenerative diseases
• human nNOS
• selective inhibition
• structure-based virtual screening
• molecular docking
• molecular dynamics simulation

Acknowledgments

The authors would like to thank the Directorate of Research and Development Resources of Kadir Has University.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions statement

Kemal Yelekci: Conceptualization, methodology, supervision, resources, writing – original draft, writing - review & editing, Sarah Boumezber: Methodology, the conductance of research, analyzing the data, visualization, original draft, writing - review & editing.

Data availability statement

All data generated or examined during this study are included in this article.