Modeling Gpcr Functional Featuresanalysis Of Activation And Signaling

While accurate modeling of the ligand binding pocket is essential for docking and screening, a global (even if low resolution) understanding of the GPCR activation and signaling mechanism would provide insight into the physiological action of GPCR drugs and identify potential allosteric sites as targets for drug discovery. The downstream effects of ligand recognition are also important for deciphering the structural basis of functional selectivity, wherein distinct ligands are able to induce different patterns of receptor activity [94]. For example, both dopamine and norepinephrine are reasonably good agonists of p2AR-mediated G protein activation, while only norepinephrine is efficient at inducing p2AR internalization [ 13] , Design of functionally selective ligands may result in drug candidates with greater efficacy and fewer side effects, but requires identification of the structural determinants of receptor activation, internalization, and G protein coupling [95]. While modeling of GPCR

activation and multimeric GPCR/G protein complexes remains in its infancy, such work provides a platform for the development of further hypotheses.

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