Toward a Universal μ-Agonist Template for Template-Based Alignment Modeling of Opioid Ligands

Abstract

Opioid ligands are a large group of G-protein-coupled receptor ligands possessing high structural diversity, along with complicated structure–activity relationships (SARs). To better understand their structural correlations as well as the related SARs, we developed the innovative template-based alignment modeling in our recent studies on a variety of opioid ligands. As previously reported, this approach showed promise but also with limitations, which was mainly attributed to the small size of morphine as a template. With this study, we set out to construct an artificial μ-agonist template to overcome this limitation. The newly constructed template contained a largely extended scaffold, along with a few special μ-features relevant to the μ-selectivity of opioid ligands. As demonstrated in this paper, the new template showed significantly improved efficacy in facilitating the alignment modeling of a wide variety of opioid ligands. This report comprises of two main parts. Part 1 discusses the general construction process and the structural features as well as a few typical examples of the template applications and Part 2 focuses on the template refinement and validation.

DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles

“…To find structural similarities between opiates, such as morphine, and 2-benzylbenzimidazole “morphinomimetics” is tempting. Although a computational study suggested similar orientations and overlapping structures for methadone and etonitazene in a hypothetical pharmacophore, experimental support of ligand–receptor interactions at atomic level for etonitazene is lacking; there are more speculations than facts. − The recent characterization by molecular dynamics simulations of the methadone-bound MOP complex revealed atomic-level interactions markedly different from those noted for morphine and some other opioids which might provide clues to the binding of 2-benzylbenzimidazole opioids . Yet the opinion cited below appears to be as valid today as it was half-a-century ago: “There are several difficulties which emerge when attempts are made to fit all analgesics to a fixed receptor site.…”

Biased Opioid Ligands

“…The SAR of Sal A was vastly studied and subsequent chemical modification allowed for the synthesis of other opioid receptors ligands, including herkinorin and kurkinorin [ 49 ]. Interestingly, these agents were described as the first non-nitrogenous MOR agonists, and displayed strong affinity toward the MOR (K i = 1.2 nM and 40 nM for Kurkinorin and Herkinorin, respectively) [ 50 ]; both compounds did not recruit β-arrestin 2 while Herkenorin in addition did not promote receptor internalization [ 30 , 48 ]. The arrestin recruitment of Herkenorin at MOR has been recently been challenged ( Table 1 ) [ 24 ].…”

Fentanyl Structure as a Scaffold for Opioid/Non-Opioid Multitarget Analgesics

“…Of particular importance, interactions of fentanyl with MOR were subject of several recent studies that used docking, molecular dynamics and other modelling techniques [ 109 , 137 , 138 , 139 , 140 , 141 , 142 , 143 ]. A useful tool for interpretation of MOR ligands’ SAR, based on template alignment, modelling have been devised, too [ 144 ]. It is also for many non-opioid GPCRs related to pain (including those discussed in this paper) that the structures have been recently solved ( Table S8 , refer to the GPCRdb service for an up-to-date and comprehensive list [ 145 ]).…”