Peer-Reviewed Journal Details
Mandatory Fields
Curtin, AM;Kinsella, GK;Stephens, JC
2015
January
Current Medicinal Chemistry
Computational Development of Selective nNOS Inhibitors: Binding Modes and Pharmacokinetic Considerations
Published
0 ()
Optional Fields
NITRIC-OXIDE SYNTHASE ENDOTHELIAL NO-SYNTHASE STRUCTURAL BASIS MONOCATIONIC INHIBITORS CALMODULIN ANTAGONIST MOLECULAR FRAGMENTS ELECTRON INJECTION CRYSTAL-STRUCTURE CEREBRAL-PALSY HYDROGEN-BOND
22
2558
2579
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.
SHARJAH
0929-8673
Grant Details