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.
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