Computational studies of competitive inhibitors of nitric oxide synthase (NOS) enzymes: towards the development of powerful and isoform-selective inhibitors.
Computational studies of competitive inhibitors of nitric oxide synthase (NOS) enzymes: towards the development of powerful and isoform-selective inhibitors.
复制标题
一氧化氮合酶（NOS）竞争性抑制剂的计算研究：致力于开发强大的异构体选择性抑制剂。
作者：
A. Tafi;Lucilla Angeli;G. Venturini;M. Travagli;F. Corelli;M. Botta
野生型和突变型NOS同工异构体与底物、中间体、抑制剂、辅因子和辅因子类似物络合的晶体结构目前是可用的。然而，由于NOS异构体的氨基酸高度保守性以及二聚体四元结构和活性位点的相似性，基于结构的异构体选择性抑制剂设计仍然是一项非常具有挑战性的任务。然而，理解这些同工异构体之间选择性的结构决定因素是设计更有效和更具选择性抑制剂的基础。基于同工酶三维结构知识的计算技术已经被应用于理解某些化合物所表现出的显著的同工酶选择性。总的来说，这些基于结构的方法，结合SAR研究，已经能够解释这种选择性的结构原因。
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.