By binding to and activating the G-protein coupled μ−, κ− and δ−opioid receptors in the central nervous
system, opiates are known to induce analgesic and sedative effects.
In particular, non-peptide opioid ligands are often used in clinical applications to induce these therapeutically beneficial
effects, due to their superior pharmacokinetics and bioavailability in comparison to endogenous neuropeptides. However,
since opioid alkaloids are highly addictive substances, it is necessary to understand the exact mechanisms of their actions,
specifically the ligand-binding properties of the target receptors, in order to safely apply opiates for therapeutic purposes.
Using an in silico molecular docking approach (AutoDock Vina) combined with two-step cluster analysis, we have
computationally obtained the docking scores and the ligand-binding pockets of twelve representative non-peptide nonendogenous
agonists and antagonists at the crystallographically identified μ-opioid receptor. Our study predicts the
existence of two main binding sites that are congruently present in all opioid receptor types. Interestingly, in terms of the
agonist or antagonist properties of the substances on the receptors, the clustering analysis suggests a relationship with the
position of the ligand-binding pockets, particularly its depth within the receptor structure. Furthermore, the binding
affinity of the substances is directly correlated to the proximity of the binding pockets to the extracellular space.
In conclusion, the results provide further insights into the structural features of the functional pharmacology of opioid
receptors, suggesting the importance of the binding position of non-peptide agonists and antagonists- specifically the
distance and the level of exposure to the extracellular space- to their dissociation kinetics and subsequent potency.