Abstract

The interaction between opioid antagonists and their cognate G protein-coupled receptors (GPCRs) is a critical determinant of therapeutic efficacy, particularly in the context of addiction and pain management. This study employed an **in silico** approach, utilizing molecular dynamics simulations and quantum chemical calculations, to systematically evaluate how the **geometrical configuration** and **molecular charge** of various opioid antagonists influence their binding affinity and kinetics to the $\mu$-opioid receptor ($\mu$-OR), a key membrane protein. The research objective was to elucidate the structural and electrostatic factors governing antagonist-receptor complex stability. Our findings reveal that specific conformational changes in the antagonist, coupled with the distribution of positive charge, significantly modulate the interaction with key residues in the $\mu$-OR binding pocket. Specifically, a more planar configuration and a localized positive charge were correlated with enhanced binding free energy and reduced dissociation rates. These results provide fundamental insights into the physicochemical principles of ligand-receptor recognition at the cellular membrane level. The derived quantitative structure-activity relationships (QSAR) offer a rational basis for the **de novo** design of novel opioid antagonists with improved pharmacological profiles.