Substitution Effect of the Trifluoromethyl Group on the Bioactivity in Medicinal Chemistry: Statistical Analysis and Energy Calculations | |
Abula, A (Abula, Amina)[ 1,2,3,4,5 ]; Xu, ZJ (Xu, Zhijian)[ 3,4,5 ]; Zhu, ZD (Zhu, Zhengdan)[ 3,4,5 ]; Peng, C (Peng, Cheng)[ 3,4,5 ]; Chen, ZQ (Chen, Zhaoqiang)[ 3,4,5 ]; Zhu, WL (Zhu, Weiliang)[ 3,4,5 ]; Aisa, HA (Aisa, Haji Akber)[ 1,2,3 ] | |
刊名 | JOURNAL OF CHEMICAL INFORMATION AND MODELING |
2020 | |
卷号 | 60期号:12页码:6242-6250 |
ISSN号 | 1549-9596 |
DOI | 10.1021/acs.jcim.0c00898 |
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记录号 | WOS:000608875100061 |
内容类型 | 期刊论文 |
源URL | [http://ir.xjipc.cas.cn/handle/365002/7780] |
专题 | 新疆理化技术研究所_资源化学研究室 |
通讯作者 | Aisa, HA (Aisa, Haji Akber)[ 1,2,3 ] |
作者单位 | 1.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, CAS Key Lab Receptor Res Drug Discovery & Design, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Key Lab Xinjiang Indigenous Med Plants Resource U, Urumqi 830011, Xinjiang, Peoples R China 5.Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Key Lab Plant Resources & Chem Arid Reg, Urumqi 830011, Xinjiang, Peoples R China |
推荐引用方式 GB/T 7714 | Abula, A ,Xu, ZJ ,Zhu, ZD ,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, A .,Xu, ZJ .,Zhu, ZD .,Peng, C .,Chen, ZQ .,...&Aisa, HA .(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, A ,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. |
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