Physical Origins of Anion Recognition in Rationally Designed Receptors: Balancing Interaction Energy and Drug Score

Abstract The rational design of synthetic anion receptors requires a detailed understanding of how different noncovalent interactions govern molecular recognition while maintaining physicochemical properties compatible with biological applications. In this work, density functional theory (DFT) calculations were employed to investigate the recognition of biologically relevant anions (acetate, chloride, and dihydrogen phosphate) by seven structurally distinct receptors. The analyses reveal that classical N–H···anion hydrogen bonds constitute the dominant contribution to the calculated interaction energy, whereas halogen bonding, C–H···anion contacts, and anion−π interactions provide secondary or cooperative stabilization depending on the receptor architecture. Complementary in silico ADMET, drug score, and toxicity analyses, integrated through a composite multicriteria ranking, identify receptor 7 as the system that best combines strong anion-binding affinities, predominantly arising from classical N–H···anion hydrogen bonding, with an excellent pharmacokinetic profile, full compliance with Lipinski’s criteria, and the absence of predicted mutagenic, tumorigenic, irritant, or reproductive risks. These findings establish quantitative relationships linking electronic structure, noncovalent interaction mechanisms, and pharmacological descriptors, providing mechanistic principles for the rational design of supramolecular receptors for biologically relevant anions. The transport ability of these receptors was not evaluated and would require experimental validation.