Parallels between the chloro and methoxy groups for potency optimization

Abstract

Small substituents such as chloro (Cl), fluoro, methyl, and methoxy (OCH₃) are often used in drug discovery to optimize ligand–protein interactions. Even though Cl is an electron-withdrawing group and OCH₃ is an electron-donating group exerting opposite effects on an aromatic ring, Cl and OCH₃ also display similarities in that they both exhibit dual electrostatic behavior. In a C–Cl bond, Cl is electronegative and adopts negative electrostatic potential, but at the same time, it has a σ-hole that is depleted of electron density and has an area of positive electrostatic potential. Similarly, the oxygen atom of OCH₃ displays negative electrostatic potential, but inductive electron-withdrawing effects bestow positive electrostatic potential at the terminal methyl group. This dual nature allows a versatile interaction with partially positive (δ⁺) and partially negative (δ⁻) regions of a protein pocket. In this study, four main types of intermolecular interactions are discussed from the vantage point of Cl and OCH₃ substituents: 1) hydrogen bonding, 2) orthogonal multipolar interactions, 3) halogen bonding and CH–O hydrogen bonding, and 4) Cl–π bonding and CH–π bonding. A comprehensive search of the PDB and analysis of X-ray co-crystal structures for each type of interaction unveiled parallels between Cl and OCH₃ in the manner in which these substituents engage with amino acid residues. The opposing electronic effects of Cl and OCH₃ substituents on an aromatic ring, along with the dual electrostatic versatility of these two groups, render them useful scouts to probe protein pockets for potency optimization.