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

蛋白质数据库 分子内力 化学 从头算 分子力学 晶格能 能量最小化 分子动力学 结晶学 配体(生物化学) 计算化学 晶体结构 立体化学 有机化学 受体 生物化学
作者
Jiahui Tong,Suwen Zhao
出处
期刊:Journal of Chemical Information and Modeling [American Chemical Society]
卷期号:61 (3): 1180-1192 被引量:23
标识
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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
刚刚
dengyan完成签到,获得积分10
1秒前
CodeCraft应助汪汪采纳,获得10
1秒前
我是老大应助刻苦的书竹采纳,获得10
2秒前
智慧爷爷发布了新的文献求助10
2秒前
酷波er应助lw777采纳,获得10
2秒前
岁月如歌发布了新的文献求助10
4秒前
bin完成签到,获得积分10
6秒前
6秒前
很好完成签到,获得积分10
7秒前
小郝已读博完成签到 ,获得积分10
7秒前
7秒前
Self-made完成签到,获得积分10
7秒前
8秒前
9秒前
10秒前
岁月如歌完成签到,获得积分10
11秒前
12秒前
joey完成签到,获得积分10
13秒前
wei完成签到 ,获得积分10
14秒前
miaojuly发布了新的文献求助10
15秒前
15秒前
研友_LXjjOZ发布了新的文献求助150
15秒前
16秒前
17秒前
18秒前
坚定馒头完成签到,获得积分10
18秒前
19秒前
19秒前
星星应助科研通管家采纳,获得30
21秒前
y924758705完成签到,获得积分20
21秒前
打打应助科研通管家采纳,获得10
21秒前
坦率的匪应助科研通管家采纳,获得10
21秒前
烟花应助科研通管家采纳,获得10
21秒前
上官若男应助科研通管家采纳,获得10
21秒前
隐形曼青应助科研通管家采纳,获得10
21秒前
NexusExplorer应助科研通管家采纳,获得10
22秒前
22秒前
YamDaamCaa应助科研通管家采纳,获得30
22秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3988868
求助须知:如何正确求助?哪些是违规求助? 3531255
关于积分的说明 11253071
捐赠科研通 3269858
什么是DOI,文献DOI怎么找? 1804822
邀请新用户注册赠送积分活动 881994
科研通“疑难数据库(出版商)”最低求助积分说明 809035