Multiple automatic base selection: Protein-ligand docking based on incremental construction without manual intervention
Multiple automatic base selection: Protein-ligand docking based on incremental construction without manual intervention
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DOI：
10.1023/a:1007913026166
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发表时间：
1997-07-01
影响因子：
3.5
通讯作者：
Lengauer, T
中科院分区：
文献类型：
--
作者：
Rarey, M;Kramer, B;Lengauer, T
解决计算机辅助药物设计中出现的分子对接问题的一种可能方法是使用增量构建方法。该方法包括三个步骤：选择分子的一部分，即所谓的碱基片段，将碱基片段置于蛋白质的活性位点，以及随后重建完整的药物分子。假设药物分子的一部分是已知的，其特异性足以成为良好的碱基片段，则该方法被证明对于大量对接实例是成功的。此外，它导致了最快的算法，灵活的对接出版至今。在大多数对接的实际应用中，必须测试大量配体对给定蛋白质的亲和力。因此，手动选择碱基片段是不实际的。另一方面，碱基片段的选择是关键的，因为只有少数选择导致低能结构。我们通过选择一组有代表性的碱基片段而不是单个片段来克服这一限制。在本文中，我们提出了一套规则和算法来自动进行这种选择。此外，我们扩展了增量构建方法来处理药物分子的多个片段。我们的研究结果表明，与多个自动化的碱基选择，对接预测的质量几乎是一样好的一个手动预选的碱基片段。此外，解决方案的集合更加多样化，并且发现了具有低得分的替代结合模式。虽然整个算法的运行时间增加，但是该方法仍然足够快以搜索大型配体数据集。
A possible way of tackling the molecular docking problem arising in computer-aided drug design is the use of the incremental construction method. This method consists of three steps: the selection of a part of a molecule a so-called base fragment, the placement of the base fragment into the active site of a protein, and the subsequent reconstruction of the complete drug molecule. Assuming that a part of a drug molecule is known, which is specific enough to be a good base fragment,the method is proven to be successful for a large set of docking examples. In addition, it leads to the fastest algorithms for flexible docking published so far. In most real-world applications of docking, large sets of ligands have to be tested for affinity to a given protein. Thus, manual selection of a base fragment is not practical. On the other hand, the selection of a base fragment is critical in that only few selections lead to a low-energy structure. We overcome this limitation by selecting a representative set of base fragments instead of a single one. In this paper, we present a set of rules and algorithms to automate this selection. In addition, we extend the incremental construction method to deal with multiple fragmentations of the drug molecule. Our results show that with multiple automated base selection, the quality of the docking predictions is almost as good as with one manually preselected base fragment. In addition, the set of solutions is more diverse and alternative binding modes with low scores are found. Although the run time of the overall algorithm increases, the method remains fast enough to search through large ligand data sets.