Title:Computational Development of Selective nNOS Inhibitors: Binding Modes and Pharmacokinetic Considerations
VOLUME: 22 ISSUE: 21
Author(s):Adam M. Curtin, Gemma K. Kinsella and John C. Stephens
Affiliation:School of Food Science and Environmental Health, College of Sciences and Health, Dublin Institute of Technology, Cathal Brugha Street, Dublin 1, Ireland., Department of Chemistry, Maynooth University, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland.
Keywords:Binding pockets, in silico, neuronal nitric oxide synthase (nNOS), selective inhibition.
Abstract:Neuronal nitric oxide synthase (nNOS) produces the key signalling mediator
nitric oxide, (NO). This gaseous, free radical molecule modulates a vast array of
biological processes, from vascular pressure to immune responses and neurological
signalling cascades. Overproduction of NO has been implicated in conditions including
Alzheimer’s disease, Parkinson’s disease and schizophrenia. Inhibition of nNOS
therefore offers a potential therapeutic approach for treatment of these conditions. This endeavour is made more complex
by the fact that there are two other isoforms of nitric oxide synthase (NOS), endothelial NOS (eNOS) and inducible
NOS (iNOS). The selectivity of nNOS inhibitors is therefore a key concern for therapeutic development. This review
explores recent advances in the field of selective nNOS inhibition. A particular focus is placed on computational
approaches towards the rational design of selective nNOS ligands with improved pharmacokinetic properties. These
ligands have been targeted at four key binding sites of the nNOS enzyme - the tetrahydrobiopterin, calmodulin, nicotinamide
adenine dinucleotide phosphate (NADPH) and arginine binding sites. The binding sites, and the compounds
used to inhibit them, will be discussed in turn, along with the computational methods which have been employed in the
field of nNOS inhibition.
