posted on 2019-10-23, 18:04authored byZhijun Wu, Victor J. Hruby
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.