Large-Scale Analysis of Bioactive Ligand Conformational Strain Energy by Ab Initio Calculation

doi:10.1021/acs.jcim.0c01197

	Large-Scale Analysis of Bioactive Ligand Conformational Strain Energy by Ab Initio Calculation
	Tong, Jiahui1,2,3,4 ; Zhao, Suwen1,2
	2021-03-22
发表期刊	JOURNAL OF CHEMICAL INFORMATION AND MODELING
ISSN	1549-9596
EISSN	1549-960X
卷号	61 期号:3 页码:1180-1192
DOI	10.1021/acs.jcim.0c01197
摘要	Ligand conformational strain energy (LCSE) plays an important role in virtual screening and lead optimization. While various studies have provided insights into LCSE for small-molecule ligands in the Protein Data Bank (PDB), conclusions are inconsistent mainly due to small datasets, poor quality control of crystal structures, and molecular mechanics (MM) or low-level quantum mechanics (QM) calculations. Here, we built a high-quality dataset (LigBoundConf) of 8145 ligand-bound conformations from PDB crystal structures and calculated LCSE at the M062X-D3/ma-TZVPP (SMD)//M062X-D3/def2-SVP(SMD) level for each case in the dataset. The mean/median LCSE is 4.6/3.7 kcal/mol for 6672 successfully calculated cases, which is significantly lower than the estimates based on molecular mechanics in many previous analyses. Especially, when removing ligands with nonaromatic ring(s) that are prone to have large LCSEs due to electron density overfitting, the mean/median LCSE was reduced to 3.3/2.5 kcal/mol. We further reveal that LCSE is correlated with several ligand properties, including formal atomic charge, molecular weight, number of rotatable bonds, and number of hydrogen-bond donors and acceptors. In addition, our results show that although summation of torsion strains is a good approximation of LCSE for most cases, for a small fraction (about 6%) of our dataset, it underestimates LCSEs if ligands could form nonlocal intramolecular interactions in the unbound state. Taken together, our work provides a comprehensive profile of LCSE for ligands in PDB, which could help ligand conformation generation, ligand docking pose evaluation, and lead optimization.
收录类别	SCIE ; EI
语种	英语
WOS研究方向	Pharmacology & Pharmacy ; Chemistry ; Computer Science
WOS类目	Chemistry, Medicinal ; Chemistry, Multidisciplinary ; Computer Science, Information Systems ; Computer Science, Interdisciplinary Applications
WOS记录号	WOS:000636723700014
出版者	AMER CHEMICAL SOC
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/126541
专题	生命科学与技术学院_博士生 iHuman研究所_PI研究组_赵素文组
通讯作者	Zhao, Suwen
作者单位	1.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China; 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China; 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Nutr & Hlth, Shanghai 200031, Peoples R China
第一作者单位	iHuman研究所; 生命科学与技术学院
通讯作者单位	iHuman研究所; 生命科学与技术学院
第一作者的第一单位	iHuman研究所
推荐引用方式 GB/T 7714	Tong, Jiahui,Zhao, Suwen. Large-Scale Analysis of Bioactive Ligand Conformational Strain Energy by Ab Initio Calculation[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2021,61(3):1180-1192.
APA	Tong, Jiahui,&Zhao, Suwen.(2021).Large-Scale Analysis of Bioactive Ligand Conformational Strain Energy by Ab Initio Calculation.JOURNAL OF CHEMICAL INFORMATION AND MODELING,61(3),1180-1192.
MLA	Tong, Jiahui,et al."Large-Scale Analysis of Bioactive Ligand Conformational Strain Energy by Ab Initio Calculation".JOURNAL OF CHEMICAL INFORMATION AND MODELING 61.3(2021):1180-1192.