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.

Drug design and repurposing with a sequence-to-drug paradigm

“…Activity cliffs are generally understood as pairs or groups of similar compounds with large differences in potency 37, 38 . Recently, Abula et al 39 proposed a dataset including 18,217 pairs of compounds and corresponding bioactivity data, with the only difference being that −CH3 is replaced by −CF3. Only 15.73% of substitutions of −CF3 for −CH3 could increase or decrease the biological activity by at least an order of magnitude, and an example is shown (Fig.…”

“…The statistical results showed that the replacement of −CH3 with −CF3 does not improve bioactivity on average 39 . However, in 15.73% of cases, substituting −CF3 for −CH3 increased or decreased the biological activity by at least an order of magnitude.…”

“…To further investigate whether TransformerCPI2.0 captures the key features of the compound and comprehensively understands compound–protein interaction, we employed TransformerCPI2.0 to predict the substitution effect of the trifluoromethyl group. We utilized a previously reported dataset 39 containing 18,217 pairs of compounds and corresponding bioactivity data with the only difference being that −CH3 is substituted by −CF3 to study this problem.…”

Design and Synthesis of Novel Podophyllotoxins Hybrids and the Effects of Different Functional Groups on Cytotoxicity

“…The compounds with the -CF 3 ( 4r , 5c ) or 10-camphor ( 4v ) group have shown the most promising apoptotic activity among the other substituents (for 4r , 5.21 μM, 4v , 2.44 μM, and 5c , 1.65 μM), which exhibited more potent activity than standard drug etoposide (12 ± 0.12 μM against A-549 [ 46 ]). Relative to other functional groups, the strong electron-sucking effect of the -CF 3 group may have increased the attraction between the protein and the PSAH [ 47 ] . On the whole, modifying R 1 or R 3 is more effective than R 2 .…”

Influence of Fluorine Substitution on Nonbonding Interactions in Selected Para‐Halogeno Anilines

“…This, in consequence, may influence and modify the micro-and macroscopic properties of the obtained molecule/ material. [7][8][9][10][11] In the last decade, increasing interest in organic halides has manifested, leading to studies concerning halogen substituent properties, especially in terms of halogen bond (XB) formation and/or playing the role of hydrogen bond (HB) acceptors. [12][13][14] The interest in halogenated derivatives is related to the peculiar properties of group 17 elements and their ability to form and/or modulate noncovalent interactions and the patterns observed in the crystalline state.…”