Unidade de Ciências Químicas e Radiofarmacêuticas, IST/ITN, Instituto Superior Técnico, Universidade Técnica de Lisboa, Estrada Nacional 10, 2686-953 Sacavém, Portugal.
J Mol Model. 2013 Apr;19(4):1537-51. doi: 10.1007/s00894-012-1677-8. Epub 2012 Dec 21.
Selective inhibition of the nitric oxide synthase isoforms (NOS) is a promising approach for the treatment of various disorders. However, given the high active site conservation among all NOS isoforms, the design of selective inhibitors is a challenging task. Analysis of the X-ray crystal structures of the NOS isoforms complexed with known inhibitors most often gives no clues about the structural determinants behind the selective inhibition since the inhibitors share the same binding conformation. Aimed at a better understanding of the structural factors responsible for selective inhibition of NOS isoforms we have performed MD simulations for iNOS, nNOS and eNOS complexed with N(ω)-NO2-L-Arg (1), and with the aminopyridine derivatives 2 and 3. The slightly better selectivity of 1 for nNOS may be assigned to the presence of extra charge-charge interactions due to its "extended" conformation. While the high affinity of 2 for iNOS can be explained by the formation of an iNOS-specific subpocket upon binding, the lack of affinity for eNOS is associated to a conformational change in Glu363. The strong van der Waals and electrostatic interactions between 3 and the active site of nNOS are most likely responsible for its higher affinity for this isoform. Owing to the elongated and narrow binding pocket of iNOS, the correct positioning of 3 over the heme group is difficult, which may account for its lower affinity toward this isoform. Brought together, our results might help to rationalize the design of selective NOS inhibitors.
选择性抑制一氧化氮合酶同工酶（NOS）是治疗各种疾病的一种很有前途的方法。然而，鉴于所有 NOS 同工酶的活性部位高度保守，选择性抑制剂的设计是一项具有挑战性的任务。分析与已知抑制剂结合的 NOS 同工酶的 X 射线晶体结构，通常不能提供关于选择性抑制背后的结构决定因素的线索，因为抑制剂具有相同的结合构象。为了更好地理解导致 NOS 同工酶选择性抑制的结构因素，我们对 iNOS、nNOS 和 eNOS 与 N(ω)-NO2-L-Arg（1）以及氨基吡啶衍生物 2 和 3 复合物进行了 MD 模拟。1 对 nNOS 的选择性稍好一些，可能归因于其“扩展”构象导致额外的电荷-电荷相互作用。虽然 2 对 iNOS 的高亲和力可以通过结合形成 iNOS 特异性亚口袋来解释，但对 eNOS 的亲和力缺乏与 Glu363 的构象变化有关。3 与 nNOS 活性位点之间的强范德华力和静电相互作用很可能是其对该同工酶亲和力较高的原因。由于 iNOS 的结合口袋狭长，3 正确定位在血红素基团上很困难，这可能是其对该同工酶亲和力较低的原因。综上所述，我们的研究结果可能有助于合理设计选择性 NOS 抑制剂。
