Pharmacological properties and biochemical mechanisms of MOR ligands might be due to different binding poses. MD Studies

Background: Central and peripheral analgesia without adverse effects rely on the identification of μ opioid agonists able to activate “basal” antinociceptive pathways. Recently developed μ selective benzo-morphan agonists not antagonized by naloxone do not activate G-proteins and β-arrestins. Which path-ways μ receptor activates? How can each of them be selectively activated? What role is played by allosteric binding sites? Methodology & Results: Molecular Modeling studies characterize amino-acids residues involved in the interaction with different classes of endogenous/exogenous ligands, with agonists and an-tagonists. Conclusions: Critical binding differences between different classes of agonists with different pharmacological profiles have been identified. The binding poses of the MML series can be relevant for the search for an antinociception without side effects.