The Key Laboratory of Plant Resources and Chemistry in Arid Regions and Key Laboratory of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, South Beijing Road 40-1, Urumqi, Xinjiang 830011, People's Republic of China.
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, People's Republic of China.
J Chem Inf Model. 2020 Dec 28;60(12):6242-6250. doi: 10.1021/acs.jcim.0c00898. Epub 2020 Dec 1.
The substitution of methyl (Me or -CH) by trifluoromethyl (TFM or -CF) is frequently used in medicinal chemistry. However, the exact effect of -CH/-CF substitution on bioactivity is still controversial. We compiled a data set containing 28 003 pairs of compounds with the only difference that -CH is substituted by -CF, and the statistical results showed that the replacement of -CH with -CF does not improve bioactivity on average. Yet, 9.19% substitution of -CH by -CF could increase the biological activity by at least an order. A PDB survey revealed that -CF prefers Phe, Met, Leu, and Tyr, while -CH prefers Leu, Met, Cys, and Ile. If we substitute the -CH by -CF near Phe, His, and Arg, the bioactivity is most probably improved. We performed QM/MM calculations for 39 -CH/-CF pairs of protein-ligand complexes and found that the -CH/-CF 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 -CF 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 -CH/-CF 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 -CH/-CF substitution, which should be useful for further drug discovery and drug design.
甲基（Me 或 -CH）被三氟甲基（TFM 或 -CF）取代在药物化学中经常被使用。然而，-CH/-CF 取代对生物活性的确切影响仍然存在争议。我们编制了一个包含 28003 对化合物的数据集，这些化合物的唯一区别是 -CH 被 -CF 取代，统计结果表明，平均而言，-CH 被 -CF 取代并不能提高生物活性。然而，-CF 对 -CH 的 9.19%取代至少可以提高一个数量级的生物活性。一个 PDB 调查显示，-CF 更喜欢苯丙氨酸、甲硫氨酸、亮氨酸和酪氨酸，而 -CH 更喜欢亮氨酸、甲硫氨酸、半胱氨酸和异亮氨酸。如果我们在苯丙氨酸、组氨酸和精氨酸附近用 -CF 取代 -CH，那么生物活性很可能会得到改善。我们对 39 对蛋白质-配体复合物的 -CH/-CF 进行了 QM/MM 计算，发现尽管平均能量差异很小，但在某些系统中，-CH/-CF 取代确实能获得很大的能量增益。苯环上的 -CF 取代在获得结合能方面可能特别有效。QM/MM 计算的最大能量提高了 4.36 kcal/mol。此外，从 MM/GBSA 计算得到的能量分解表明，-CH/-CF 取代的巨大能量增益主要是由静电能或溶剂化自由能驱动的。这些发现可能为 -CH/-CF 取代的生物活性谱提供一些启示，这对于进一步的药物发现和药物设计应该是有用的。
