Automatic and efficient decomposition of two-dimensional structures of small molecules for fragment-based high-throughput docking
Automatic and efficient decomposition of two-dimensional structures of small molecules for fragment-based high-throughput docking
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DOI：
10.1021/jm060838i
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发表时间：
2006-12-14
影响因子：
7.3
通讯作者：
Caflisch, Amedeo
中科院分区：
文献类型：
--
作者：
Kolb, Peter;Caflisch, Amedeo
计算机程序 DAIM（分子分解和识别）已开发用于自动分解小分子库中的化合物，以进行基于片段的对接以及数据库分析。此处，DAIM 在源自配体-蛋白质复合物的已知晶体结构的 130 个配体上进行了评估。分解和新的基于指纹的识别技术用于选择锚片段进行对接。对接结果表明，DAIM选择优于基于大小或随机的片段选择。为了评估分析大型文库片段组成的有用性，将 DAIM 应用于约 185 万种市售化合物的集合。有趣的是，我们发现源自 185 万个分子分解的最常见的环状和非环状片段集与 5120 种已知药物的库中最常见的片段有很大的重叠。 DAIM 已通过基于片段的高通量对接成功用于 β-分泌酶和 EphB4 激酶抑制剂的计算机筛选。简要讨论了从头配体设计的未来可能的应用。
The computer program DAIM (Decomposition and Identification of Molecules) has been developed to automatically break up compounds in small-molecule libraries for fragment-based docking as well as database analysis. Here, DAIM is evaluated on 130 ligands derived from known crystal structures of ligand-protein complexes. The decomposition and a new fingerprint-based identification technique are used to select anchor fragments for docking. The docking results show that the DAIM selection is superior to size-based or random selection of fragments. To evaluate the usefulness for analyzing the fragment composition of a large library, DAIM is applied to a collection of about 1.85 million commercially available compounds. Interestingly, it is found that the set of most frequent cyclic and acyclic fragments originating from the decomposition of the 1.85 million molecules shows a large overlap with the most frequent fragments in a library of 5120 known drugs. DAIM has been successfully used in the in silico screening for inhibitors of beta-secretase and EphB4 kinase by fragment-based high-throughput docking. Possible future applications for de novo ligand design are briefly discussed.