Cebranopadol: An Assessment for Its Biased Activation Potential at the Mu Opioid Receptor by DFT, Molecular Docking and Molecular Dynamic Simulation Studies

Abstract Cocaine use disorder is a psychiatric condition affecting millions of people worldwide. Up till now, there are no FDA approved medications reported against this disorder. Previous pharmacological studies suggested that, simultaneously targeting all types of opioid receptors, some agonistically while others antagonistically have been proven a much useful strategy for the treatment of cocaine addiction. Recent evidence indicated that a novel agonist cebranopadol has a high binding affinity towards Nociceptin opioid receptor (NOP) and Mu opioid receptor (MOP), and partial affinity with Kappa opioid receptor (KOP) and Delta opioid receptor (DOP). Interestingly, in vivo studies revealed that cebranopadol blocked the cocaine seeking in animal models. In the present study, quantum chemical calculations were performed to calculate various thermodynamic parameters of cebranopadol using density functional theory. Flexible docking was performed to rationalize the molecular basis of cis and trans isomers of cebranopadol. Further, the atomistic description of activation mechanism of MOP receptor by cebranopadol investigated by sub‐microsecond timescale molecular dynamic (MD) simulation. Our results revealed that the operating mode of the activation switch composed of Trp293 6.48 and Asn328 7.45 residues, was accountable for down‐ and up‐regulation, respectively, of the β‐arrestin signaling. This particular conformational change in turn affected the G‐protein‐biased activation of MOP receptor. Cebranopadol stabilized the Asn328 7.45 by mediating halogen bond formation. According to best of our knowledge, this is the first mechanistic study of cebranopadol with MOP receptor using the quantum mechanical calculations and MD simulations to explain the inhibition of cocaine addiction.