G Protein β γ Subunits as Targets for Small Molecule Therapeutic Development
Alan V. Smrcka, David M. Lehmann and Axel L. Dessal
Affiliation: Departments of Pharmacology,Physiology, Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Keywords: G protein β γ subunits, GRK2ct, computational screening, G protein-coupled receptor, small molecule targeting, protein-protein interactions, G protein signaling
G proteins mediate the action of G protein coupled receptors (GPCRs), a major target of current pharmaceuticals and a major target of interest in future drug development. Most pharmaceutical interest has been in the development of selective GPCR agonists and antagonists that activate or inhibit specific GPCRs. Some recent thinking has focused on the idea that some pathologies are the result of the actions of an array of GPCRs suggesting that targeting single receptors may have limited efficacy. Thus, targeting pathways common to multiple GPCRs that control critical pathways involved in disease has potential therapeutic relevance. G protein β γ subunits released from some GPCRs upon receptor activation regulate a variety of downstream pathways to control various aspects of mammalian physiology. There is evidence from cell- based and animal models that excess Gβ γ signaling can be detrimental and blocking Gβ γ signaling has salutary effects in a number of pathological models. Gβ γ regulates downstream pathways through modulation of enzymes that produce cellular second messengers or through regulation of ion channels by direct protein-protein interactions. Thus, blocking Gβ γ functions requires development of small molecule agents that disrupt Gβ γ protein interactions with downstream partners. Here we discuss evidence that small molecule targeting Gβ γ could be of therapeutic value. The concept of disruption of protein-protein interactions by targeting a “hot spot” on Gβ γ is delineated and the biochemical and virtual screening strategies for identification of small molecules that selectively target Gβ γ functions are outlined. Evaluation of the effectiveness of virtual screening indicates that computational screening enhanced identification of true Gβ γ binding molecules. However, further refinement of the approach could significantly improve the yield of Gβ γ binding molecules from this screen that could result in multiple candidate leads for future drug development.
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