Nitric oxide synthase and structure-based inhibitor design

Once it was discovered that the enzyme nitric oxide synthase (NOS) is responsible for the biosynthesis of NO, NOS became a drug target. Particularly important is the over production of NO by neuronal NOS (nNOS) in various neurodegenerative disorders. After the various NOS isoforms were identified, inhibitor development proceeded rapidly. It soon became evident, however, that isoform selectivity presents a major challenge. All 3 human NOS isoforms, nNOS, eNOS (endothelial NOS), and iNOS (inducible NOS) have nearly identical active site structures thus making selective inhibitor design especially difficult. Of particular importance is the avoidance of inhibiting eNOS owing to its vital role in the cardiovascular system. This review summarizes some of the history of NOS inhibitor development and more recent advances in developing isoform selective inhibitors using primarily structure-based approaches.