中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
Substitution Effect of the Trifluoromethyl Group on the Bioactivity in Medicinal Chemistry: Statistical Analysis and Energy Calculations

文献类型:期刊论文

作者Abula, Amina1,2,3,4,5; Xu, Zhijian1,4,5; Zhu, Zhengdan1,4,5; Peng, Cheng1,4,5; Chen, Zhaoqiang1,4,5; Zhu, Weiliang1,4,5; Aisa, Haji Akber1,2,3
刊名JOURNAL OF CHEMICAL INFORMATION AND MODELING
出版日期2020-12-28
卷号60期号:12页码:6242-6250
ISSN号1549-9596
DOI10.1021/acs.jcim.0c00898
通讯作者Xu, Zhijian(zjxu@simm.ac.cn) ; Zhu, Weiliang(wlzhu@simm.ac.cn) ; Aisa, Haji Akber(haji@ms.ajb.ac.cn)
英文摘要The substitution of methyl (Me or -CH3) by trifluoromethyl (TFM or -CF3) is frequently used in medicinal chemistry. However, the exact effect of -CH3/-CF3 substitution on bioactivity is still controversial. We compiled a data set containing 28 003 pairs of compounds with the only difference that -CH3 is substituted by -CF3, and the statistical results showed that the replacement of -CH3 with -CF3 does not improve bioactivity on average. Yet, 9.19% substitution of -CH3 by -CF3 could increase the biological activity by at least an order. A PDB survey revealed that -CF3 prefers Phe, Met, Leu, and Tyr, while -CH3 prefers Leu, Met, Cys, and Ile. If we substitute the -CH3 by -CF3 near Phe, His, and Arg, the bioactivity is most probably improved. We performed QM/MM calculations for 39 -CH3/-CF3 pairs of protein-ligand complexes and found that the -CH3/-CF3 substitution does achieve a large energy gain in some systems, although the mean energy difference is subtle, which is consistent with the statistical survey. The -CF3 substitution on the benzene ring could be particularly effective at gaining binding energy. The maximum improvements in energy achieved -4.36 kcal/mol by QM/MM calculation. Moreover, energy decompositions from MM/GBSA calculations showed that the large energy gains for the -CH3/-CF3 substitution are largely driven by the electrostatic energy or the solvation free energy. These findings may shed some light on the biological activity profile for -CH3/-CF3 substitution, which should be useful for further drug discovery and drug design.
WOS关键词DRUG DESIGN ; FLUORINE ; BOND ; DATABASE ; STATES
资助项目National Natural Science Foundation of China[31870717] ; National Key Research and Development Program of China[2016YFA0502301]
WOS研究方向Pharmacology & Pharmacy ; Chemistry ; Computer Science
语种英语
WOS记录号WOS:000608875100061
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/295944]  
专题中国科学院上海药物研究所
通讯作者Xu, Zhijian; Zhu, Weiliang; Aisa, Haji Akber
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Key Lab Plant Resources & Chem Arid Reg, Urumqi 830011, Xinjiang, Peoples R China
3.Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Key Lab Xinjiang Indigenous Med Plants Resource U, Urumqi 830011, Xinjiang, Peoples R China
4.Chinese Acad Sci, CAS Key Lab Receptor Res Drug Discovery & Design, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714
Abula, Amina,Xu, Zhijian,Zhu, Zhengdan,et al. Substitution Effect of the Trifluoromethyl Group on the Bioactivity in Medicinal Chemistry: Statistical Analysis and Energy Calculations[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2020,60(12):6242-6250.
APA Abula, Amina.,Xu, Zhijian.,Zhu, Zhengdan.,Peng, Cheng.,Chen, Zhaoqiang.,...&Aisa, Haji Akber.(2020).Substitution Effect of the Trifluoromethyl Group on the Bioactivity in Medicinal Chemistry: Statistical Analysis and Energy Calculations.JOURNAL OF CHEMICAL INFORMATION AND MODELING,60(12),6242-6250.
MLA Abula, Amina,et al."Substitution Effect of the Trifluoromethyl Group on the Bioactivity in Medicinal Chemistry: Statistical Analysis and Energy Calculations".JOURNAL OF CHEMICAL INFORMATION AND MODELING 60.12(2020):6242-6250.

入库方式: OAI收割

来源:上海药物研究所

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