GPCRs homology modeling

The feasibility of GPCR homology models for structure-based virtual screening was initially demonstrated in a few retrospective [65,66] and prospective applications [67, 68[. Varady et al. [69] reported on the discovery of novel and potent dopamine D3 ligands from a hybrid pharmacophore- and structure-based approach. Of the 20 tested compounds, 8 showed K values <1 [xM. 

It is generally considered that a sequence identity below 30% is insufficient to build a useful homology model. Success stories of GPCR homology modeling... 

Costanzi, S. (2008) On the applicability of GPCR homology models to computer-aided drug discovery a comparison between in sUico and crystal structures of the beta2-adrenergic receptor. Journal of Medicinal Chemistry, 51 (10), 2907-2914. 

For targets that lack structural information, such as GPCRs or ion channels, a pharmacophore model or multiple pharmacophore models for different series of compounds can explain SAR and guide the synthesis of new analogs. Alternatively, homology models based on bacteriorhodopsin have been used to explain the interactions of small molecules with GPCRs. 

The widely accepted model of GPCR homologous desensitisation describes a system in which the agonist-activated receptors couple to G proteins to induce a cellular response, and are subsequently phosphorylated by members of GRK, with GRKs invariably phosphorylating serine or threonine residues on the third intracellular loop or COOH terminus of the receptors (Reiter and Lefkowitz 2006). The GRK family consists of seven different genes. 

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