Structure-Based Design in the GPCR Target Space

M.      Kontoyianni; Z.      Liu

Abstract

The G protein-coupled receptors (GPCRs) are membrane proteins that transmit signals via G-protein coupling. They have long been the target of small molecule therapeutics accounting for 30% of the launched drug targets. They are subdivided into several classes, with rhodopsins corresponding to the largest class. Furthermore, a high number of new rhodopsin-like GPCR proteins are included in the druggable genome, thus they are projected to continue being of value to the pharmaceutical and biotechnology sectors. We present a comprehensive review of the structural information pertaining to GPCRs, in light of the most recently deposited crystal structures, along with comparisons of the available to-date structures at different activation states. Finally, computational approaches to GPCR modeling are discussed in conjunction with critical perspectives regarding feasibility and limitations.

Keywords: G-protein Coupled Receptors, Homology Modeling, Virtual Screening, Model-Building, Critical Assessment of Structure Prediction, Docking, Structure-Based Drug Design, Activation Mechanism, Conserved Motifs, Mutagenesis