In silico Insights on the Allosteric Modulation of the µ-Opioid Receptor and G protein Complex in the Presence of Agonist Ligand BU72 and Potential Positive Allosteric Modulator BMS-986121

The G protein-coupled receptor (GPCR) µ-opioid receptor (µOR) is one of several drug targets of commercially available therapeutics for pain. Various opioid drugs like morphines have been associated to numerous substance abuse-related deaths around the world. A better alternative to avoid this undesirable side effect is by targeting allosteric sites. In addition, understanding the underlying mechanism of allosteric ligands in µOR is highly sought for better drug optimizations. Using molecular dynamics, the allosteric behavior of the µOR and G protein complex in the presence of agonist ligand BU72 and potential positive allosteric modulator (PAM) BMS-986121 was probed by observing residue-residue contacts formation and breakage. It was found that G protein residues D959, L349, and K963 participate in the interprotein contact formation between µOR and G protein. Moreover, orthosteric binding site residues D83, Y84, and H233 polar interactions were verified to be critical not only on the agonist ligand binding, but also in the allosteric communication of the protein complex. Also, the overall decrease on the number of contacts was observed after mutations, which can trigger the opening of the orthosteric binding site. Rationalization of allosteric modulation in µ-opioid receptor-G protein complex may improve drug discovery schemes and strategies for allosteric drugs including other targets in the GPCR protein families.