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

doi:10.1186/1471-2105-11-545

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Bioactive conformational generation of small molecules: A comparative analysis between force-field and multiple empirical criteria based methods
	Bai, Fang 2,4; Liu, Xiaofeng 1,3; Li, Jiabo 6; Zhang, Haoyun 1,3; Jiang, Hualiang1,3,5 ; Wang, Xicheng 2; Li, Honglin 1,3
刊名	BMC BIOINFORMATICS
	2010-11-04
卷号	11
ISSN号	1471-2105
DOI	10.1186/1471-2105-11-545
文献子类	Article
英文摘要	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.
资助项目	Special Fund for Major State Basic Research Project[2009CB918501] ; National Natural Science Foundation of China[20803022] ; National Natural Science Foundation of China[20721003] ; Shanghai Committee of Science and Technology[09dZ1975700] ; Shanghai Committee of Science and Technology[10431902600] ; Shanghai Committee of Science and Technology[08JC1407800] ; 863 Hi-Tech Program of China[2007AA02Z304] ; Major National Scientific and Technological Project of China[2009ZX09501-001] ; 111 Project[B07023] ; State Key Laboratory of Phytochemistry and Plant Resources in West China[00000000] ; Shanghai Rising-Star Program[10QA1401800] ; Fundamental Research Funds for the Central Universities[00000000]
WOS关键词	PROTEIN-BOUND LIGANDS ; GENETIC ALGORITHM ; CONFORMER GENERATION ; EFFICIENT ; SEARCH ; SPACE ; BINDING ; OMEGA
WOS研究方向	Biochemistry & Molecular Biology ; Biotechnology & Applied Microbiology ; Mathematical & Computational Biology
语种	英语
出版者	BIOMED CENTRAL LTD
WOS记录号	WOS:000284627300001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278724]
专题	药物发现与设计中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Wang, Xicheng
作者单位	1.E China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China; 2.Dalian Univ Technol, State Key Lab Struct Anal Ind Equipment, Dept Engn Mech, Dalian 116023, 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
推荐引用方式 GB/T 7714	Bai, Fang,Liu, Xiaofeng,Li, Jiabo,et al. Bioactive conformational generation of small molecules: A comparative analysis between force-field and multiple empirical criteria based methods[J]. BMC BIOINFORMATICS,2010,11.
APA	Bai, Fang.,Liu, Xiaofeng.,Li, Jiabo.,Zhang, Haoyun.,Jiang, Hualiang.,...&Li, Honglin.(2010).Bioactive conformational generation of small molecules: A comparative analysis between force-field and multiple empirical criteria based methods.BMC BIOINFORMATICS,11.
MLA	Bai, Fang,et al."Bioactive conformational generation of small molecules: A comparative analysis between force-field and multiple empirical criteria based methods".BMC BIOINFORMATICS 11(2010).