Substitution Effect of the Trifluoromethyl Group on the Bioactivity in Medicinal Chemistry: Statistical Analysis and Energy Calculations

Abstract

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.