BCL::Conf: small molecule conformational sampling using a knowledge based rotamer library.
BCL::Conf: small molecule conformational sampling using a knowledge based rotamer library.
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DOI：
10.1186/s13321-015-0095-1
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发表时间：
2015
影响因子：
8.6
通讯作者：
Meiler J
中科院分区：
文献类型：
--
作者：
Kothiwale S;Mendenhall JL;Meiler J
构象采样进行使用来自晶体结构数据库的明确片段构象。来自数据库的分子被分解成片段，并且最有可能的构象/旋转异构体被用于对感兴趣的分子的相应子结构进行采样。小分子与蛋白质靶标的相互作用取决于其采用互补的三维结构的能力。因此，完整和快速预测小分子可以采样的构象空间对于基于结构和配体的药物发现算法如小分子对接或三维定量结构-活性关系都是至关重要的。在这里，我们已经推导出一个数据库的小分子片段经常在实验结构中采样的剑桥结构数据库和蛋白质数据库。类似于用于蛋白质构象空间的快速取样的氨基酸侧链旋转异构体文库，这些片段的可能构象被存储为“旋转异构体”。明确的片段考虑到多个扭转键之间的相关性和扭转配置文件上的取代基的效果。小分子的构象系综，然后可以通过重组片段旋转异构体与蒙特卡洛搜索策略。BCL：：Conf与其他构象生成器方法（包括Confgen、莫伊、Omega和RDKit）在其恢复实验测定的小分子蛋白结合构象、构象集合多样性和采样率的能力方面进行了基准测试。BCL：：Conf恢复了至少一种构象，对于Vernalis基准数据集中99%的小分子，其均方根偏差为2 μ m或更好。“旋转异构体”方法将允许BCL：：Conf集成到各自的计算生物学程序中，如Rosetta。本文的在线版本（doi：10.1186/s13321-015-0095-1）包含补充材料，可供授权用户使用。
Conformation sampling is carried out using explicit fragment conformations derived from crystallographic structure databases. Molecules from the database are decomposed into fragments and most likely conformations/rotamers are used to sample correspondng sub-structure of a molecule of interest. The interaction of a small molecule with a protein target depends on its ability to adopt a three-dimensional structure that is complementary. Therefore, complete and rapid prediction of the conformational space a small molecule can sample is critical for both structure- and ligand-based drug discovery algorithms such as small molecule docking or three-dimensional quantitative structure–activity relationships. Here we have derived a database of small molecule fragments frequently sampled in experimental structures within the Cambridge Structure Database and the Protein Data Bank. Likely conformations of these fragments are stored as ‘rotamers’ in analogy to amino acid side chain rotamer libraries used for rapid sampling of protein conformational space. Explicit fragments take into account correlations between multiple torsion bonds and effect of substituents on torsional profiles. A conformational ensemble for small molecules can then be generated by recombining fragment rotamers with a Monte Carlo search strategy. BCL::Conf was benchmarked against other conformer generator methods including Confgen, Moe, Omega and RDKit in its ability to recover experimentally determined protein bound conformations of small molecules, diversity of conformational ensembles, and sampling rate. BCL::Conf recovers at least one conformation with a root mean square deviation of 2 Å or better to the experimental structure for 99 % of the small molecules in the Vernalis benchmark dataset. The ‘rotamer’ approach will allow integration of BCL::Conf into respective computational biology programs such as Rosetta. The online version of this article (doi:10.1186/s13321-015-0095-1) contains supplementary material, which is available to authorized users.