Many marketed drugs for treating CNS disorders have complex G Protein-Coupled Receptors (GPCR) polypharmacology leading either to favorable pharmaceutical outcomes or undesired adverse events. We have curated and integrated binding data for thousands of GPCR ligands extracted from both ChEMBL and PDSP databases. We have developed and extensively validated a panel of Quantitative Structure Activity Relationships (QSAR) classification models for 34 different receptors (i.e., the QSARome). Most models achieved high prediction performances according to a rigorous 5-fold external validation. The QSARome was applied to assess the GPCR binding profiles of 13 external drugs not present in the modeling set, reaching an external prediction accuracy of 70.5%. The QSARome was also used to identify novel compounds with unique target-selective GPCR binding profiles. The QSARome panel is integrated within the Chembench webportal (chembench.mml.unc.edu) providing an effective in silico means to search for novel molecules with the desired GPCR polypharmacology.

QSARome of GPCRs

243rd National Meeting (2012)

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