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.
Because of their strong electron-rich properties, nucleic acids (NAs) can theoretically serve as halogen bond (XB) acceptors. From a PDB database survey, Kolář found that no XBs are formed between noncovalent ligands and NAs. Through statistical database analysis, quantum-mechanics/molecular-mechanics (QM/MM) optimizations, and energy calculations, we find that XBs formed between natural NAs and noncovalent ligands are primarily underestimated and that NAs can serve as XB acceptors to interact with noncovalent halogen ligands. Finally, through energy calculations, natural bond orbital analysis, and noncovalent interaction analysis, XBs are confirmed in 13 systems, among which two systems (445D and 4Q9Q) have relatively strong XBs. In addition, on the basis of energy scanning of four model systems, we explore the geometric rule for XB formation in NAs. This work will inspire researchers to utilize XBs in rational drug design targeting NAs.
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