Cebranopadol (CBP) is a novel analgesic acting as agonist at the nociceptin (NOP) and μ-opioid (MOP) receptors, exhibiting high potency and efficacy as an antinociceptive and antihypersensitive drug. The binding conformation and the dynamical interactions of CBP with the NOP receptor have been investigated by molecular docking, molecular dynamics (MD) in the microsecond time scale, and hybrid quantum mechanics/molecular mechanics (QM/MM). CBP binds to the NOP receptor as a bidentate ligand of the aspartate D130 3,32 by means of both its fluoroindole and dimethyl nitrogens. Starting from the known crystal structure of the inactive state of the receptor, in complex with the antagonist compound-24 (NOP-C24) the comparative analysis of 1 μs MD trajectories of the NOP-C24 complex itself and the NOP-free and NOP-CBP complexes provides new insights on the already known microswitches related to receptor activation, in the frame of the extended ternary complex model. The agonist acts by destabilizing the inactive conformation of the NOP receptor, by inducing a conformational change of M134 3,36 , which allows W276 6,48 to flip around its 2 dihedral, going in close proximity to the receptor hydrophobic core (T138 3,40 , P227 5,50 , F272 6,44 ), which is known to be fundamental for the activation of the opioid receptors. A complete rational picture is also provided for the role of N133 3,35 and W276 6,48 undergoing critical conformational changes related to an anticooperativity effect, i.e. the well-known role of sodium as negative modulator of agonist binding. Finally, the movement of residue Y319 7,53 belonging to the NPxxY motif is also induced by the binding of the agonist in the inactive state, opening a gate for a water channel just as upon receptor activation.
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