Fluorine multipolar interaction: Toward elucidating its energetics in binding recognition

Abstract

Multipolar interactions have gained attention due to their roles in molecular recognition events of chemical and biological systems. Structural evidence suggests that the fluorine multipolar interaction is a favorable molecular interaction in the paradigm of protein-ligand recognition. With an aim to understand its propensity and energetics in ligand-protein assembly, we mined the “Pfizer protein-ligand X-ray structure database” with three-dimensional constraints for the presence of such interactions. A set of transformation rules were applied to generate their corresponding matched molecular pairs (MMPs) that bear hydrogen(s) in place of the interacting fluorine(s). Biological activities were retrieved from our internal data warehouse for the MMPs with and without the ability to form the multipolar interaction. On the basis of the observed potency differences we determined that the free energy gain associated with the fluorine multipolar interaction is relatively modest, ∼0.3–0.6kcal/mol, and the net impact on lipophilic efficiency (LipE) is essentially neutral. A general guideline for medicinal chemists has emerged from this study, enabling a more rational employment of this type of interaction in molecular design.