文献类型：期刊文献

英文题名：Bioactive conformational generation of small molecules: A comparative analysis between force-field and multiple empirical criteria based methods

作者：Bai, Fang[1,4];Liu, Xiaofeng[2,3];Li, Jiabo[6];Zhang, Haoyun[2,3];Jiang, Hualiang[2,3,5];Wang, Xicheng[1];Li, Honglin[2,3]

机构：[1]Dalian Univ Technol, State Key Lab Struct Anal Ind Equipment, Dept Engn Mech, Dalian 116023, Peoples R China;[2]E China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[3]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab Chem Biol, Shanghai 200237, Peoples R China;[4]Dalian Univ Technol, Fac Chem Environm & Biol Sci & Technol, Dalian 116023, Peoples R China;[5]Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China;[6]Accelrys Inc, San Diego, CA 92121 USA

年份：2010

卷号：11

外文期刊名：BMC BIOINFORMATICS

收录：;EI(收录号：20131116100625);WOS:【SCI-EXPANDED(收录号:WOS:000284627300001)】；

基金：This work was supported by the Special Fund for Major State Basic Research Project (grant 2009CB918501), the National Natural Science Foundation of China (grants 20803022 and 20721003), the Shanghai Committee of Science and Technology (grants 09dZ1975700, 10431902600 and 08JC1407800), the 863 Hi-Tech Program of China (grant 2007AA02Z304), the Major National Scientific and Technological Project of China (grant 2009ZX09501-001), the 111 Project (grant B07023) and the Fund of State Key Laboratory of Phytochemistry and Plant Resources in West China. Honglin Li is also sponsored by Shanghai Rising-Star Program (grant 10QA1401800) and the Fundamental Research Funds for the Central Universities.

语种：英文

外文关键词：Equivalent circuits - Evolutionary algorithms - Conformations

摘要：Background: Conformational sampling for small molecules plays an essential role in drug discovery research pipeline. Based on multi-objective evolution algorithm (MOEA), we have developed a conformational generation method called Cyndi in the previous study. In this work, in addition to Tripos force field in the previous version, Cyndi was updated by incorporation of MMFF94 force field to assess the conformational energy more rationally. With two force fields against a larger dataset of 742 bioactive conformations of small ligands extracted from PDB, a comparative analysis was performed between pure force field based method (FFBM) and multiple empirical criteria based method (MECBM) hybrided with different force fields. Results: Our analysis reveals that incorporating multiple empirical rules can significantly improve the accuracy of conformational generation. MECBM, which takes both empirical and force field criteria as the objective functions, can reproduce about 54% (within 1 angstrom RMSD) of the bioactive conformations in the 742-molecule testset, much higher than that of pure force field method (FFBM, about 37%). On the other hand, MECBM achieved a more complete and efficient sampling of the conformational space because the average size of unique conformations ensemble per molecule is about 6 times larger than that of FFBM, while the time scale for conformational generation is nearly the same as FFBM. Furthermore, as a complementary comparison study between the methods with and without empirical biases, we also tested the performance of the three conformational generation methods in MacroModel in combination with different force fields. Compared with the methods in MacroModel, MECBM is more competitive in retrieving the bioactive conformations in light of accuracy but has much lower computational cost. Conclusions: By incorporating different energy terms with several empirical criteria, the MECBM method can produce more reasonable conformational ensemble with high accuracy but approximately the same computational cost in comparison with FFBM method. Our analysis also reveals that the performance of conformational generation is irrelevant to the types of force field adopted in characterization of conformational accessibility. Moreover, post energy minimization is not necessary and may even undermine the diversity of conformational ensemble. All the results guide us to explore more empirical criteria like geometric restraints during the conformational process, which may improve the performance of conformational generation in combination with energetic accessibility, regardless of force field types adopted.