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