Identification of Withanolide-M and Stigmasterol as Potent neuroprotectant and Dual inhibitor of Inducible/Neuronal Nitric Oxide Synthase by Structure-Based Virtual Screening
Journal Title: JOURNAL OF BIOLOGICAL ENGINEERING RESEARCH AND REVIEW - Year 2017, Vol 4, Issue 1
Abstract
Nitric oxide (NO) is an important intracellular signaling molecule, generated by catalysis from nitric oxide synthases (NOSs). In the face of NO playing beneficial roles, its overproduction by the neuronal nitric oxide synthase (nNOS) or inducible nitric oxide synthase (iNOS) is detrimental in neurological disorders, whereas that derived from the endothelial nitric oxide synthase (eNOS) is beneficial. Therefore, dual inhibition of iNOS and nNOS without inhibiting eNOS is a promising neuroprotective approach for combating stroke. Withania somnifera (WS) has been used for centuries as a nerve tonic and Nootropic agents in Ayurveda. Present structure-based molecular docking study was performed to identify novel, potent and dual iNOS/nNOS inhibitor by screening the Withania somnifera constituents. A ligand database containing 36 phytochemicals present in W. somnifera along with nNOS and iNOS selective inhibitor was molecularly docked onto catalytic heme domain of three NOS isoforms. This approach identified two phytosteroids withanolide-M and stigmasterol that have higher selectivity, bind with the lower binding energy and established a number of H -bonds or hydrophobic contacts with the catalytic oxygenase domain of iNOS and nNOS than their selective inhibitors (AT2 and S19). Their suitability for Lipinski’s Rule of Five, the ability to cross the Blood-Brain Barrier (BBB), high human intestinal absorption score make them a potent possible neurotherapeutic agent to combat neurological disorders mediated by nNOS and iNOS activation
Authors and Affiliations
Gaurav Kumar, Sumedha Mukherjee, Ranjana Patnaik
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