Evaluation of an inverse molecular design algorithm in a model binding site
Evaluation of an inverse molecular design algorithm in a model binding site
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DOI：
10.1002/prot.22226
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发表时间：
2009-04-01
影响因子：
2.9
通讯作者：
Tidor, Bruce
中科院分区：
文献类型：
--
作者：
Huggins, David J.;Altman, Michael D.;Tidor, Bruce
计算分子设计是现代药物发现的有用工具。虚拟筛选是一种对接化合物库的各个成员然后进行评分的方法。与这种正向方法相反，逆向方法从片段构建化合物，从而优化计算的亲和力或相关特性的组合。我们最近开发了一种新的药物设计逆向方法，该方法基于采用物理势函数的死端消除和 A* 算法。该方法已应用于组合构建的小分子配体文库，以设计高亲和力 HIV-1 蛋白酶抑制剂（Altman 等人，J Am Chem Soc 2008；130：6099-6013）。在这里，我们使用经过充分研究的细胞色素 c 过氧化物酶 W191G 突变体评估了新方法。该突变体具有带电结合袋，并已用于评估其他设计方法。结果表明，总体而言，新的逆向方法在区分粘合剂和非粘合剂方面表现出色。对于一些个别案例，评分不准确会导致误报。其中大多数涉及带电胺、苯胺离子和酚的错误溶剂化能估计，这种情况之前已在各种评分算法中观察到。有趣的是，虽然通常期望逆向方法识别文库中的一些但不是全部结合物，但由于构象搜索有限，这些结果显示了已知结合物的极好的覆盖率，同时仍然显示出对非结合物的强烈区分。
Computational molecular design is a useful tool in modern drug discovery. Virtual screening is an approach that docks and then scores individual members of compound libraries. In contrast to this forward approach, inverse approaches construct compounds from fragments, such that the computed affinity, or a combination of relevant properties, is optimized. We have recently developed a new inverse approach to drug design based on the dead-end elimination and A* algorithms employing a physical potential function. This approach has been applied to combinatorially constructed libraries of small-molecule ligands to design high-affinity HIV-1 protease inhibitors (Altman et al., J Am Chem Soc 2008;130:6099-6013). Here we have evaluated the new method using the well-studied W191G mutant of cytochrome c peroxidase. This mutant possesses a charged binding pocket and has been used to evaluate other design approaches. The results show that overall the new inverse approach does an excellent job of separating binders from non-binders. For a few individual cases, scoring inaccuracies led to false positives. The majority of these involve erroneous solvation energy estimation for charged amines, anilinium ions, and phenols, which has been observed previously for a variety of scoring algorithms. interestingly, although inverse approaches are generally expected to identify some but not all binders in a library, due to limited conformational searching, these results show excellent coverage of the known binders while still showing strong discrimination of the nonbinders.