A Structural Feature of the Non-Peptide Ligand Interactions with Mice Mu-Opioid Receptors

Abstract

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.

Molecular insights into the interaction of hemorphin and its targets

“…Hydrophobic interactions were formed between camel LVV-hemorphin-7 and Tyr328, which is consistent with a previous report that indicated that hemorphin interacts with Tyr326 of mouse MOR 49,51,56 . The interaction with Trp320 on TM7 is also consistent with previous studies 51,57,58 . Interestingly, camel LVV-hemorphin-7 interacted with key residues in the binding pocket for a longer duration than non-camel hemorphin (Fig.…”

“…LVVYPWTRRF interacted for a longer duration than LVVYPWTQRF with Thr220, Glu231, and Tyr328 in the human MOR model. The corresponding residues in the murine MOR – Thr200, Glu299, and Tyr326 – have been shown to interact with agonists 49,51,56,58 . RMSF values were found to be high for IL-3 residues when bound to camel LVV-hemorphin-7.…”

Mu-Opioid receptor biased ligands: A safer and painless discovery of analgesics?

“…Several studies have explored the binding modes of different ligands at the μ, δ-, and κ-OR [5,61–63]. For instance, based on docking models, Noori et al proposed two main binding regions in opioid receptors that might correlate with agonists and antagonists in terms of depth within the receptor, following a relationship between the affinity of the ligand and the proximity to the extracellular side [64]. Similarly, it could be hypothesized that the binding recognition profile of biased ligands might be characteristic and allow one to discriminate biased from nonbiased ligands.…”