Probing molecular docking in a charged model binding site
Probing molecular docking in a charged model binding site
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DOI：
10.1016/j.jmb.2006.01.034
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发表时间：
2006-04-14
影响因子：
5.6
通讯作者：
Shoichet, BK
中科院分区：
文献类型：
--
作者：
Brenk, R;Vetter, SW;Shoichet, BK
利用模型结合位研究了分子对接过程中的电荷相互作用。这个简单的位置，一个小的(180埃(3))工程化的空腔，在环色素c过氧化物酶(CCP)中，带负电荷并完全掩埋在溶剂中，使我们能够在一个许多常见的对接近似不适用的系统中探索静电能量和配体去溶能之间的平衡。一个包含大约5300个分子的数据库被对接到这个空腔中。对已知配体和诱饵的回溯性测试表明，总的来说，静电相互作用和去溶能之间的平衡被捕捉到了。更有趣的是未来的对接屏幕，它们寻找新的配体，特别是那些可能揭示对接和能量方法问题的对接屏幕。基于5300化合物数据库的筛选，获得了得分高和得分低的分子，并对其进行了结合测试。在测试的16种新的高得分化合物中，有15种被观察到结合。所有这些都是小杂环阳离子。测定了其中几种配体的结合常数，它们的范围在20微米到60微米之间，确定了其中10种与蛋白质形成的络合物的晶体结构。观察到的配体几何构型与对接预测的几何构型非常吻合。还测试了几个得分较低的烷基氨基阳离子，发现它们是结合的。这些分子的低对接分数归因于带电氨基的相对较高的电荷密度和相应的较高的脱溶惩罚。当确定这些配体的络合结构时，观察到一个结合水分子与空腔的氨基和主链羰基相互作用。这种水分子减轻了脱溶惩罚，并提高了相对于停靠屏幕中使用的“裸露”位置的相互作用能量。最后，还对六个得分较低的中性分子进行了测试，以期寻找错误的负面预测。虽然其中大多数没有结合，但有两个(苯酚和3-氟儿茶酚)结合。这两个配体与空穴位置的络合物的晶体结构表明了它们结合的原因。事实上，这些中性分子确实结合在一起，这与之前在这个位置的结果相矛盾，并与烷基胺一起提供了有启发性的假阴性，有助于识别我们评分功能中的弱点。文中考虑了这些算法的几点改进。(C)2006爱思唯尔有限公司。保留所有权利。
A model binding site was used to investigate charge-charge interactions in molecular docking. This simple site, a small (180 angstrom(3)) engineered cavity in cyctochrome c peroxidase (CCP), is negatively charged and completely buried from solvent, allowing us to explore the balance between electrostatic energy and ligand desolvation energy in a system where many of the common approximations in docking do not apply. A database with about 5300 molecules was docked into this cavity. Retrospective testing with known ligands and decoys showed that overall the balance between electrostatic interaction and desolvation energy was captured. More interesting were prospective docking screens that looked for novel ligands, especially those that might reveal problems with the docking and energy methods. Based on screens of the 5300 compound database, both high-scoring and low-scoring molecules were acquired and tested for binding. Out of 16 new, high-scoring compounds tested, 15 were observed to bind. All of these were small heterocyclic cations. Binding constants were measured for a few of these, they ranged between 20 mu M and 60 mu M. Crystal structures were determined for ten of these ligands in complex with the protein. The observed ligand geometry corresponded closely to that predicted by docking. Several low-scoring alkyl amino cations were also tested and found to bind. The low docking score of these molecules owed to the relatively high charge density of the charged amino group and the corresponding high desolvation penalty. When the complex structures of those ligands were determined, a bound water molecule was observed interacting with the amino group and a backbone carbonyl group of the cavity. This water molecule mitigates the desolvation penalty and improves the interaction energy relative to that of the "naked" site used in the docking screen. Finally, six low-scoring neutral molecules were also tested, with a view to looking for false negative predictions. Whereas most of these did not bind, two did (phenol and 3-fluorocatechol). Crystal structures for these two ligands in complex with the cavity site suggest reasons for their binding. That these neutral molecules do, in fact bind, contradicts previous results in this site and, along with the alkyl amines, provides instructive false negatives that help identify weaknesses in our scoring functions. Several improvements of these are considered. (c) 2006 Elsevier Ltd. All rights reserved.