A Study on Docking Mode of HIV Protease and Their Inhibitors
A Study on Docking Mode of HIV Protease and Their Inhibitors
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DOI：
10.2477/jchemsoft.7.103
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发表时间：
2001-09
期刊：
影响因子：
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通讯作者：
栄一 赤穂;G. Morris;D. Goodsell;David Wong;A. Olson
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文献类型：
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作者：
栄一 赤穂;G. Morris;D. Goodsell;David Wong;A. Olson
提出将推定的配体抑制剂结合到已知受体位点的可行方法的能力对于成功的基于结构的药物设计是至关重要的。计算机对接方法是以许多不同的方式将配体和受体分子定位或“对接”在一起，然后通过应用合理的评价函数对每个取向进行评分。AutoDock3.0是一个无偏型对接程序，其中用户不必将配体引导到活性位点，但系统会在配体以随机方式放置后找到最佳位置。合成的衍生物的完整的抑制剂（inh 1）的HIV蛋白酶进行了研究，其对接模式相比，其Ki值。在这些衍生物中，inh3transs和inh6H被发现是比其他人更强大的HIV蛋白酶抑制剂。应用分子力学相互作用能计算得到的吉布斯自由能与一系列HIV蛋白酶抑制剂的实验抑制效力得到的吉布斯自由能进行了比较，发现两者之间有相当好的相关性。基于计算结果和实验结果之间的这种良好的相关性，考虑到在针对HIV蛋白酶的inh 1和inh 8的对接研究中检测到具有相当大体积的未利用的碳亲和区域（或疏水区域）的事实，对Syphilis绘制的化合物进行了计算实验。这些化合物的叔丁基被各种疏水侧链取代。其中，具有苄基的化合物表现出最低的对接能。由于本文的目标之一是进行计算药物设计实验以研究潜在的HIV蛋白酶抑制剂，因此作者希望将临床研究工作留给这些领域的专业知识。
The capability to propose feasible ways of binding a putative ligand inhibitor to a known receptor site is crucial to the successful structure-based drug design. A computer docking approach is to position or “dock" ligand and receptor molecules together in many different ways and then score each orientation by applying a reasonable evaluation function. AutoDock3.0 is an unbiased type docking program in which a user does not have to direct a ligand to an active site, but the system finds an optimal position after a ligand is placed in a random manner. Synthesized derivatives of the intact inhibitor (inh1) of HIV protease were investigated for their docking modes as compared with their Ki values. Among the derivatives, inh3trans and inh6H were found to be more powerful inhibitors of HIV protease than the others. Gibbs free energy calculated by applying molecular mechanics interaction energies was compared with the one obtained by using experimental inhibitory potencies for a series of HIV protease inhibitors, and a fairly good correlation was found between the two. Based on this favorable correlationship between the computational and the experimental results, the computational experiments were pursued for the compounds drawn by Sybyl taking into consideration the fact that unexploited carbon affinity regions (or hydrophobic regions) with sizable volume were detected on the docking study of inh1 and inh8 against HIV protease. Those were compounds with a t-butyl substituted by various hydrophobic side chains. Among those a compound with a benzyl group exhibited the lowest docking energy. Since one of the goals of this paper was to perform the computational drug-design experiment to investigate potential HIV protease inhibitors, the authors would like to leave the clinical investigational work for the expertise of those areas.