Towards the Rational Design of Opioids with Desired Binding Kinetics

Abstract

Opioid receptors are classical pharmacological targets and the object of intense research towards improved analgesics with reduced side effects. High-resolution X-ray crystal structures of all four opioid receptor subtypes - the mu (MOP), kappa (KOP), delta (DOP), and nociceptin (NOP) opioid receptors - have recently provided direct information about the molecular determinants of opioid binding affinity. Yet, little information is available about the kinetics of opioid-receptor binding, which may be as important as, or even more important than, affinity for the rational design of efficacious opioid-based therapeutics.By accelerating transitions between low-energy states, enhanced molecular dynamics techniques are especially suited to gain atomic-level insight into opioid receptor recognition and binding. Here, we used multiple-walker well-tempered metadynamics to investigate the binding of classical opioid receptor ligands to the mouse MOP receptor. We find that the first interaction between the ligand and MOP involves residue D218 in the extracellular loop 2 and residues of transmembrane (TM) helix 2. Analysis of the lowest-energy binding pathways reveals an additional intermediate metastable state in which the ligand positions itself in a region that is partially occupied by JDTic in the corresponding KOP crystal structure, forming interactions with residues in TM2 and TM3.We used the free-energies resulting from our simulations to derive estimates of binding affinity and transition rates along the characterized opioid binding pathways, as well as ligand on- and off-rates. Given the reasonable agreement between the calculated estimates and published experimental values, and the provided powerful insights into molecular determinants of opioid-receptor binding kinetics, these types of simulation hold great promise for the rational design of opioids with desired binding kinetics.