Nitric oxide: modeling of synthesis and inhibition

Abstract

Nitric oxide (NO) is a ubiquitous biological messenger involved in a variety of physiological processes that acts as a signal transducer but also exerts a variety of regulatory and cytostatic functions. Nitric oxide synthases (NOSs) are flavohaem enzymes that function broadly in human health and disease. The nitric-oxide synthases are modular, cofactorcontaining enzymes, divided into a heme-containing oxygenase domain and an FMN- and FAD-containing reductase domain. The oxidation of L-Arginine to Lcitruline and NO consist of two sequential mechanistic distinct steps. The oxidation involves three-electron and NO is synthesized from one of the two N-guanidinium atoms of L-Arg. Although crystal structures are now available for NOS isoforms alone or complex with the substrate, the reaction mechanism is still unclear. Overproduction of NO can cause several biological disorders. Selective inhibition of one of the NOS isoforms becomes a major goal for pharmacological researchers since each isoform plays a role on different pathological or physiological processes. Recently, NO have been related to migraine headaches, Parkinson’s disease, and Alzheimer’s disease, involving neuronal NOS (nNOS). The molecular aspects of both the reaction mechanism of NO formation and the structure-activity relationship of NOS inhibitors are discussed.