Computational Studies of Competitive Inhibitors of Nitric Oxide Synthase (NOS) Enzymes: Towards the Development of Powerful and Isoform-Selective Inhibitors

Abstract

Crystallographic structures of wild-type and mutant NOS isoforms complexed with substrate, intermediate, inhibitor, cofactor, and cofactor analogs are currently available. However, because of the high level of amino-acid conservation and the consequent similarity in dimeric quaternary structure as well as in the active site of NOS isoforms, structure-based isoform-selective inhibitor design is still a very challenging task. Nevertheless, the comprehension of the structural determinants for selectivity among the isoforms is fundamental for the design of further potent and more selective inhibitors. Computational techniques, based on the knowledge of the tridimensional structure of the isozymes, have been already applied to understand the significant isoform selectivity shown by some compounds. Collectively these structure-based approaches, in combination with SAR studies, have been able to explain the structural reasons of this selectivity.

Selective Acetamidine-Based Nitric Oxide Synthase Inhibitors: Synthesis, Docking, and Biological Studies

“…13 According to their different mechanism of action, these compounds may be divided into two major groups: molecules targeting the L-Arg binding site and acting as competitive inhibitors of the natural substrate, and inhibitors of the enzyme dimerization. 14 The first class of compounds is characterized by the presence of a guanidine-like moiety, able to mimic the L-Arg guanidine−protein interactions in the binding site. Owing to their structural similarities with LArg, earlier substrate-competitive inhibitors block the three isoforms indiscriminately, with unacceptably severe side effects.…”

Selective Inhibition of iNOS by Benzyl‐ and Dibenzyl Derivatives of N‐(3‐Aminobenzyl)acetamidine

“…More recent studies have focused on the design and synthesis of non-amino acid analogues, such as amino heterocycles, amidines, guanidines, isoquinolinamines, and isothioureas. [11][12][13][14] We previously reported the synthesis, biological evaluation, and docking studies of a series of N-substituted acetamidines, [15] structurally related to the leading scaffold W1400 [16] (1), a potent and selective iNOS inhibitor. Starting from docking results previously obtained, and with the aim of extending the study of possible ligand-enzyme interactions, we have now evaluated the effect of the introduction of several substituents in ortho, meta or para positions of the leading scaffolds 2 and 3, differing from 1 by the amino substitution at the 3-aminomethyl group with one or two benzylic groups.…”

Computational Development of Selective nNOS Inhibitors: Binding Modes and Pharmacokinetic Considerations

“…A large portion of contemporary literature in the area of nNOS inhibition has focused on arginine analogues [32,56,57]. These compounds act as competitive inhibitors of the NOS isoforms by mimicking the interactions of the enzyme's natural substrate.…”