Summary And Conclusions

The solution of GPCR crystal structures is a technically challenging, financially costly, and labor-intensive process. As additional structures are determined, it is critical that computational methodologies be in place to maximize the benefit of the experimental data to the drug discovery community. Energy-based conformational refinement of existing crystallographic data is an important first step toward generating a protonated, full-atom model suitable for docking. LGM with judicious use of experimental restraints can extend a given structure to describe interactions for other ligand/receptor complexes and GPCR types. As discussed here, very accurate conformational predictions may be made that enable selective VLS for agonists or antagonists. Computational modeling for orphan GPCRs and the Classes B and C receptor families provides a lower resolution view of the receptor structure and allosteric binding pocket; these models may facilitate drug discovery when paired with pharmacophore or SAR data. Finally, though significant gaps remain in our understanding of the mechanisms underlying receptor activation and signaling, computational modeling of these functional features provides a platform for examining experimental data and developing new hypotheses.

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