Abstract

Opioid receptors, critical G protein-coupled receptors (GPCRs) embedded in the cell membrane, are primary targets for pain management, with antagonists playing a vital role in reversing opioid effects. Understanding the molecular determinants of antagonist-receptor binding is essential for rational drug design. This study aimed to perform an **in silico evaluation** of how the **geometrical configuration** and **charge** of various opioid antagonists influence their binding affinity and selectivity to the opioid receptor family. Using a combination of molecular docking simulations and molecular dynamics (MD) analyses, we modeled the interaction of a library of antagonists with the receptor binding pocket. Key findings indicate that specific antagonist conformations, particularly those involving the protonated amine group, are crucial for establishing stable hydrogen bonds and electrostatic interactions within the transmembrane helices. Furthermore, the overall charge distribution significantly modulated the binding free energy, with subtle changes in geometry leading to substantial differences in predicted efficacy. These results provide novel, atomic-level insights into the structure-activity relationship of opioid antagonists, highlighting the importance of precise molecular geometry and charge in optimizing ligand design for targeted pharmacological intervention at the cellular membrane.