Virtual screening against metalloenzymes for inhibitors and substrates
Virtual screening against metalloenzymes for inhibitors and substrates
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DOI：
10.1021/bi050801k
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发表时间：
2005-09-20
期刊：
影响因子：
2.9
通讯作者：
Shoichet, BK
中科院分区：
文献类型：
--
作者：
Irwin, JJ;Raushel, FM;Shoichet, BK
分子对接使用受体的三维结构来筛选潜在配体的小分子数据库，通常基于能量互补性。对于许多计算非键相互作用的对接评分函数，由于金属-配体相互作用的部分共价性质，金属酶是具有挑战性的。为了研究如何以及分子对接可以识别潜在的配体的金属酶使用“标准”的评分功能，我们对接了MDL药物数据报告（MDDR），一个功能注释的数据库95 000个小分子，对X射线晶体结构的五种金属酶。这些酶包括三种锌蛋白酶、一种铁酶的镍类似物和一种钼金属酶。对接程序的能力，回顾性地丰富注释的配体作为高得分命中每种酶和计算适当的几何形状进行了评估。在所有五个系统中，MDDR内的注释配体相对于随机富集至少20倍。为了前瞻性地测试该方法，针对ZINC数据库的片段样子集筛选了第六个靶标，即来自脆弱拟杆菌的锌β-内酰胺酶。我们从对接排名前50位的配体中购买并测试了15个化合物，发现5个抑制剂的表观Ki值小于120 μ M，其中最好的是2 μ M。一个更雄心勃勃的测试仍然是预测第七个目标的实际底物，来自缺陷假单胞菌的锌依赖性磷酸三酯酶。筛选可用的化学品目录（ACD）确定25硫代磷酸酯作为潜在的底物排名前100位的化合物。其中八个，所有以前未表征的这种酶，获得和测试，并通过实验证实所有作为底物。这些结果表明，一个简单的，非共价评分功能，可用于确定至少一些金属酶的抑制剂。
Molecular docking uses the three-dimensional structure of a receptor to screen databases of small molecules for potential ligands, often based on energetic complementarity. For many docking scoring functions, which calculate nonbonded interactions, metalloenzymes are challenging because of the partial covalent nature of metal-ligand interactions. To investigate how well molecular docking can identify potential ligands of metalloenzymes using a "standard" scoring function, we have docked the MDL Drug Data Report (MDDR), a functionally annotated database of 95 000 small molecules, against the X-ray crystal structures of five metalloenzymes. These enzymes included three zinc proteases, the nickel analogue of an iron enzyme, and a molybdenum metalloenzyme. The ability of the docking program to retrospectively enrich the annotated ligands as high-scoring hits for each enzyme and to calculate proper geometries was evaluated. In all five systems, the annotated ligands within the MDDR were enriched at least 20 times over random. To test the approach prospectively, a sixth target, the zinc beta-lactamase from Bacteroides fragilis, was screened against the fragment-like subset of the ZINC database. We purchased and tested 15 compounds from among the top 50 top-ranked ligands from docking, and found 5 inhibitors with apparent K-i values less than 120 mu M, the best of which was 2 mu M. A more ambitious test still was predicting actual substrates for a seventh target, a Zn-dependent phosphotriesterase from Pseudomonas diminuta. Screening the Available Chemicals Directory (ACD) identified 25 thiophosphate esters as potential substrates within the top 100 ranked compounds. Eight of these, all previously uncharacterized for this enzyme, were acquired and tested, and all were confirmed experimentally as substrates. These results suggest that a simple, noncovalent scoring function may be used to identify inhibitors of at least some metalloenzymes.