Can an optimization/scoring procedure in ligand-protein docking be employed to probe drug-resistant mutations in proteins?
Can an optimization/scoring procedure in ligand-protein docking be employed to probe drug-resistant mutations in proteins?
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DOI：
10.1016/s1093-3263(01)00091-2
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发表时间：
2001-01-01
影响因子：
2.9
通讯作者：
Cao, ZW
中科院分区：
文献类型：
--
作者：
Chen, YZ;Gu, XL;Cao, ZW
简单的配体-蛋白质结构优化和结合评估程序已常规用于高速配体-蛋白质对接研究。在这项工作中，我们研究了这种优化/评分程序是否有助于指示蛋白质中可能的耐药突变。研究了与多种抑制剂复合的三种野生型酶（HIV-1 蛋白酶、HIV-1 逆转录酶和结核分枝杆菌 H37Rv 烯酰基-ACP 还原酶）的晶体结构。通过使用分子建模软件 SYBYL 将突变引入到这些结构中。突变体复合物的结构优化和评分是通过类似于最近对接研究中使用的程序进行的（Wang 等人，1999）。将计算结果与观察到的耐药性数据和非耐药仿制品的概况进行比较。研究的大多数突变显示能量变化的方向与观察到的抗性数据所指示的方向相同。发现 50% 的极性到极性或非极性到非极性突变与观察到的耐药性数据定性相关。范德华相互作用解释了大部分这些变化，这与结构研究的结论一致。实质上，对于大多数极性到非极性或非极性到极性突变，计算结果和观察数据之间存在较大偏差，这是由于我们的程序中配体-蛋白质相互作用建模和评分的缺陷造成的。我们的结果表明，优化/对接评分程序除了应用于筛选活性化合物外，还可用于定性探测极性到极性或非极性到非极性耐药突变。可能需要更准确地描述配体-蛋白质相互作用以及使用自由能、微扰和泊松-玻尔兹曼等方法，以进一步提高预测质量。 (C) 2001 年，爱思唯尔科学公司。
A simple ligand-protein structural optimization and binding evaluation procedure has been routinely used in high-speed ligand-protein docking studies. In this work, we examine whether such an optimization/scoring procedure is useful in indicating possible drug-resistant mutations in proteins. Crystal structures of three wild-type enzymes (HIV-1 protease, HIV-1 reverse transcriptase, and Mycobacterium tuberculosis H37Rv enoyl-ACP reductase) complexed to a variety, of inhibitors are studied. Mutations are introduced into these structures by using the molecular modeling software, SYBYL. Structural optimization and scoring of a mutant complex is conducted by, a procedure similar to that used in a recent docking study, (Wang et al., 1999). The computed results are compared with observed drug resistance data and the profile of nonresistant Imitations. Most mutations studied show an energy change in the same direction as those indicated by, observed resistance data. 50% of the polar to polar or nonpolar to nonpolar mutations are found to correlate qualitatively with observed drug resistance data. Van der Waals interactions account for most of these changes, which is in agreement with conclusions from structural studies. Substantially, larger deviations are found between computed results and observed data for most polar to nonpolar or nonpolar to polar mutations, which result from deficiency in modelling and scoring ligand-protein interactions in our procedure. Our results suggest that an optimization/docking scoring procedure is useful for qualitatively probing polar to polar or nonpolar to nonpolar resistant mutations in addition to its application in screening active compounds. More accurate description of ligand-protein interactions and the use of methods such as free energy, perturbation and Poisson-Boltzmann may be needed to further improve the quality of prediction. (C) 2001 by Elsevier Science Inc,.