Modeling the Active Conformation of Human µ Opioid Receptor
Agnieszka A. Kaczor, Damian Bartuzi and Dariusz Matosiuk
Affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland.
Keywords: GPCR activation, GPCRs, homology modeling, molecular docking, opioid receptors.
G protein-coupled receptors (GPCRs) family, including opioid receptors, constitute one of the most important
groups of drug targets. Chance for successful drug design for GPCRs can be increased by the availability of 3D structures
of these proteins in their inactive (to bind antagonists) or active (to bind agonists) conformation. However, to date only
few X-ray structures of GPCR-agonist complexes are known. The presented study aims to investigate the usage of single
and multiple templates approach for homology modeling of the µ opioid receptor in its active conformation. The models
are first assessed regarding their stereochemical and geometric correctness. Next, docking of two MOR agonists makes it
possible to find the model with the most favourable conformation of binding site side chains. The study indicates that
careful choice of templates and their proper alignment is particularly important in multi-template homology modeling, and
that models based on a single template can be comparatively good as models based on multiple templates. Furthermore, it
proves that use of only one template or template set may not be enough for obtaining the best possible homology model,
and that building a set of models based on different template sets with subsequent comparative analysis can be beneficial
approach. In particular, such a strategy can be useful to construct a model in a particular activation state or to reproduce
ligand-specific rearrangement pattern, when supported with experimental data.
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