ZL006及其衍生物与nNOS PDZ相互作用的理论研究
Theoretical Investigation on the Interaction of ZL006 and Its Derivatives with nNOS PDZ Domain
摘要： 缺血性脑卒中是严重危害人类健康和生命安全的常见疾病。前期研究发现，化合物ZL006能够特异性阻断突触后密度蛋白-95(PSD-95)与神经元型一氧化氮合酶（nNOS）的偶联，从而减轻缺血性脑卒中后的神经细胞凋亡和损伤，发挥神经保护作用。为了探究ZL006及其衍生物中各种结构因素（如空间位阻、电负性、亲酯亲水性等）对其与nNOS PDZ相互作用的影响，本文分别应用自动和手动分子对接、传统的以及可极化的分子力场，对比研究了ZL006（4-(3,5-二氯-2-羟基苄氨基)-2-羟基苯甲酸）及其9个衍生物，分析了它们与nNOS PDZ之间的相互作用方式和强度。研究发现：手动对接后，药物分子作用在"THR-123、ARG-121、GLY-56、GLN-59、ILE-58、GLU-53"组成的活性口袋内。在此基础上，通过可极化的FF03力场计算得到的药物-蛋白相互作用强度，与实验上得到的药物活性顺序较为一致。ZL006及其衍生物通过分子间氢键与蛋白质相互作用，二者之间的静电作用力起主导作用。化合物的结构因素对其与蛋白质的相互作用具有重要的影响，电负性极性基团的增多，有利于化合物与蛋白质之间形成氢键作用，能够增强化合物与蛋白的作用；而羧基和羟基的甲酯化和醚化均不利用化合物与蛋白质复合物的形成，进而降低药物的活性。
关键词： 药物-蛋白质相互作用；神经元型一氧化氮合酶(nNOS)；PDZ结构域抑制剂；分子对接；可极化模型
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发表医学论文网
LI Ting， JIANG Nan*
（ School of Pharmacy,Nanjing Medical University ,Nanjing 210029； ）
Abstract： Ischemic stroke is a common disease which seriously affects the human health and life safety. In our previous works, it was found that ZL006 could play the neuroprotective effect by specifically blocking the coupling between postsynaptic density-95 (PSD-95) and neuronal nitric oxide synthase (nNOS), which could reduce ischemic stroke after the nerve cell damage and apoptosis. In order to investigate the influence of various structural factors (including stereo-hindrance effect, electronegativity, lipotropy and hydrophily) on the drug-protein interaction, automatic and manual docking, conventional and polarizable force fields were employed to investigate the interaction modes and strengths of ZL006 and its derivatives with nNOS PDZ. It was shown that the selected ligands could act with nNOS in the active region consisting of THR-123、ARG-121、GLY-56、GLN-59、ILE-58、GLU-53. On the basis of these obtained complexes, the drug-protein interaction energies calculated by polarizable FF03 force field showed good agreement with the experimentally obtained drug activity. The complexation between drugs and protein relied on the intermolecular hydrogen bonding, and the electrostatic interactions play a dominant role in stabilizing the complexes. The structures of the drugs had important effect. The polar groups with high electronegativity facilitated the formation of hydrogen bonds and strengthened the drug-protein interactions. The methyl esterification and etherification of carbonyl and hydroxyl groups played an instabilization role in the complex and decreased the activity of the drugs.
Keywords： Drug-protein interaction; Neuronal nitric oxide synthase (nNOS); Postsynaptic density domain inhibitors; Molecular docking; Polarization model
