Studies of g protein-coupled receptor structure and function: Receptor modeling and synthesis of bivalent ligands

Fiona Michelle McRobb
<span title="2017-02-06">2017</span>
G protein-coupled receptors (GPCRs) are therapeutically significant proteins and are targeted by over 25% of FDA approved drugs. GPCRs are highly druggable and are involved in a diverse range of disease states and, as such, are of immense interest to the pharmaceutical industry. GPCRs play an important role in cell signaling, mediating signals across the cell membrane. Recent advances in the high resolution X-ray crystallography of GPCRs make structure-based drug design significantly more
more &raquo; ... le. Additionally, increased understanding of the arrangement of GPCRs in the cell membrane indicates that many GPCRs are likely to form dimers or higher order oligomers. In fact, dimerization is believed to be a common feature to GPCRs and may represent a novel therapeutic target for numerous disease states. In this thesis, recent high resolution crystal structures of several class A GPCRs have been used in the development and evaluation of new homology models of pharmaceutically relevant GPCRs. Additionally, a series of homobivalent ligands have been developed as pharmacological tools to investigate GPCR dimerization. Homology models for several therapeutically significant GPCRs were developed using the high resolution X-ray crystal structure of the β2-adrenergic receptor as a template (Chapter 2; McRobb, F. M. et al. J. Chem. Inf. Model. 2010, 50, 626-637). Techniques to optimize the orthosteric binding site, such as flexible receptor docking and loop refinement, were investigated. Small scale virtual screening was undertaken to evaluate the developed homology models for use in a structure-based drug design campaign. Of the nine homology models developed, six showed moderate to good enrichment in virtual screening experiments (5-HT1BR, 5-HT2AR, 5-HT2CR, D2R, D3R and M1 mAChR). These newly developed aminergic GPCR homology models supplement the limited number of freely available GPCR homology models. It is hoped that these models will provide a better starting point for structure-based drug design. As a continuation of ou [...]
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