Su A I, Lorber D M, Weston G S, Baase W A, Matthews B W, Shoichet B K
Department of Molecular Pharmacology & Biological Chemistry, Northwestern University, Chicago, Illinois 60611-3008, USA.
Proteins. 2001 Feb 1;42(2):279-93. doi: 10.1002/1097-0134(20010201)42:2<279::aid-prot150>3.0.co;2-u.
Molecular docking programs screen chemical databases for novel ligands that fit protein binding sites. When one compound fits the site well, close analogs typically do the same. Therefore, many of the compounds that are found in such screens resemble one another. This reduces the variety and novelty of the compounds suggested. In an attempt to increase the diversity of docking hit lists, the Available Chemicals Directory was grouped into families of related structures. All members of every family were docked and scored, but only the best scoring molecule of a high-ranking family was allowed in the hit list. The identity and scores of the other members of these families were recorded as annotations to the best family member, but they were not independently ranked. This family-based docking method was compared with molecule-by-molecule docking in screens against the structures of thymidylate synthase, dihydrofolate reductase (DHFR), and the cavity site of the mutant T4 lysozyme Leu99 --> Ala (L99A). In each case, the diversity of the hit list increased, and more families of known ligands were found. To investigate whether the newly identified hits were sensible, we tested representative examples experimentally for binding to L99A and DHFR. Of the six compounds tested against L99A, five bound to the internal cavity. Of the seven compounds tested against DHFR, six inhibited the enzyme with apparent K(i) values between 0.26 and 100 microM. The segregation of potential ligands into families of related molecules is a simple technique to increase the diversity of candidates suggested by database screens. The general approach should be applicable to most docking methods. Proteins 2001;42:279-293.
分子对接程序会在化学数据库中筛选适合蛋白质结合位点的新型配体。当一种化合物与该位点匹配良好时，其类似物通常也能如此。因此，在此类筛选中发现的许多化合物彼此相似。这降低了所建议化合物的多样性和新颖性。为了增加对接命中列表的多样性，将可用化学物质目录按相关结构家族进行了分组。每个家族的所有成员都进行了对接和评分，但命中列表中只允许排名靠前家族的得分最高分子入选。这些家族中其他成员的身份和得分被记录为得分最高家族成员的注释，但它们不单独排名。在针对胸苷酸合成酶、二氢叶酸还原酶（DHFR）以及突变型T4溶菌酶Leu99→Ala（L99A）的腔位点结构进行的筛选中，将这种基于家族的对接方法与逐个分子对接进行了比较。在每种情况下，命中列表的多样性都增加了，并且发现了更多已知配体家族。为了研究新鉴定的命中物是否合理，我们对代表性实例进行了实验测试，以检测其与L99A和DHFR的结合情况。在针对L99A测试的六种化合物中，有五种与内腔结合。在针对DHFR测试的七种化合物中，有六种抑制该酶，其表观K(i)值在0.26至100 microM之间。将潜在配体分离成相关分子家族是一种增加数据库筛选所建议候选物多样性的简单技术。这种通用方法应适用于大多数对接方法。《蛋白质》2001年；42卷：279 - 293页。
