Rational Design of Orthogonal Multipolar Interactions with Fluorine in Protein–Ligand Complexes

Abstract

Multipolar interactions involving fluorine and the protein backbone have been frequently observed in protein–ligand complexes. Such fluorine–backbone interactions may substantially contribute to the high affinity of small molecule inhibitors. Here we found that introduction of trifluoromethyl groups into two different sites in the thienopyrimidine class of menin–MLL inhibitors considerably improved their inhibitory activity. In both cases, trifluoromethyl groups are engaged in short interactions with the backbone of menin. In order to understand the effect of fluorine, we synthesized a series of analogues by systematically changing the number of fluorine atoms, and we determined high-resolution crystal structures of the complexes with menin. We found that introduction of fluorine at favorable geometry for interactions with backbone carbonyls may improve the activity of menin–MLL inhibitors as much as 5- to 10-fold. In order to facilitate the design of multipolar fluorine–backbone interactions in protein–ligand complexes, we developed a computational algorithm named FMAP, which calculates fluorophilic sites in proximity to the protein backbone. We demonstrated that FMAP could be used to rationalize improvement in the activity of known protein inhibitors upon introduction of fluorine. Furthermore, FMAP may also represent a valuable tool for designing new fluorine substitutions and support ligand optimization in drug discovery projects. Analysis of the menin–MLL inhibitor complexes revealed that the backbone in secondary structures is particularly accessible to the interactions with fluorine. Considering that secondary structure elements are frequently exposed at protein interfaces, we postulate that multipolar fluorine–backbone interactions may represent a particularly attractive approach to improve inhibitors of protein–protein interactions.

Molecular insights into Aβ42 protofibril destabilization with a fluorinated compound D744: A molecular dynamics simulation study

“…The visualization of snapshots from the MD trajectory highlight that C―F bond of D744 interacts with a CO moiety of F20 (chain A) of Aβ 42 protofibril through orthogonal multipolar interaction which is consistent with the results reported from molecular docking studies. The optimal geometry and orientation of ligand are important criteria that decide about the feasibility of C―F···CO interactions . The orthogonal geometry of C―F bond relative to the peptide backbone is responsible for these unique types of interactions in the binding region where hydrogen bond interactions do not exist.…”

Taking Advantage of Hydrophobic Fluorine Interactions for Self‐Assembled Quantum Dots as a Delivery Platform for Enzymes

“…[7] Thes tability of these nanostructures was reported to be higher than expected because of the unique hydrophobicity and lipophilicity of the fluorine atoms,which confer stronger interactions than other noncovalent bonds. [9,10] These studies showed ad ramatic increase in the binding affinity towards most of the proteins and enzymes upon fluorine substitution. [9,10] These studies showed ad ramatic increase in the binding affinity towards most of the proteins and enzymes upon fluorine substitution.…”

Structure and Energetics of Ligand–Fluorine Interactions with Galectin‐3 Backbone and Side‐Chain Amides: Insight into Solvation Effects and Multipolar Interactions

“…In particular, orthogonal multipolar C−F⋅⋅⋅C=O interactions with both peptide backbone and side‐chain carbonyl groups have been described as important for fluorine. Amides are abundant in proteins, and orthogonal multipolar fluorine–amide interactions between ligand fluorines and backbone amides (Figure a) have been reported . The fluorine–amide interaction is proposed to arise from an attractive dipole interaction between the C−F and C=O groups, and the geometric preferences have also been determined in a model system using chemical double‐mutant cycles.…”

“…Such distinct fluorophilic environments in proteins are peptide bonds, which can participate in multipolar C−F⋅⋅⋅H−N, C−F⋅⋅⋅C=O, and C−F⋅⋅⋅H−Cα interactions, as well as the side‐chain amide moieties of Asn and Gln . Fluorines enhance ligand affinity by interacting with both the polar electropositive and the hydrophobic groups in proteins . In particular, orthogonal multipolar C−F⋅⋅⋅C=O interactions with both peptide backbone and side‐chain carbonyl groups have been described as important for fluorine.…”

“…The same study analyzed eight previously determined systems containing such interactions and found a positive relationship between fluorine–amide interactions and affinity for six of them (2‐ to 24‐fold increases). In contrast, for two systems the introduction of such interactions could be related to modest decreases in inhibitory activity, leading to the conclusion that predictions based solely on geometrical criteria may have limitations …”