Activity Models of Key GPCR Families in the Central Nervous System: A Tool for Many Purposes

Abstract

G protein-coupled receptors (GPCRs) are targets of many drugs, of which ∼25% are indicated for central nervous system (CNS) disorders. Drug promiscuity affects their efficacy and safety profiles. Predicting the polypharmacology profile of compounds against GPCRs can thus provide a basis for producing more precise therapeutics by considering the targets and the antitargets in that family of closely related proteins. We provide a tool for predicting the polypharmacology of compounds within prominent GPCR families in the CNS: serotonin, dopamine, histamine, muscarinic, opioid, and cannabinoid receptors. Our inhouse algorithm, "iterative stochastic elimination" (ISE), produces high-quality ligand-based models for agonism and antagonism at 31 GPCRs. The ISE models correctly predict 68% of CNS drug-GPCR interactions, while the "similarity ensemble approach" predicts only 33%. The activity models correctly predict 56% of reported activities of DrugBank molecules for these CNS receptors. We conclude that the combination of interactions and activity profiles generated by screening through our models form the basis for subsequent designing and discovering novel therapeutics, either single, multitargeting, or repurposed.

Orphan G Protein-Coupled Receptor GPR37 as an Emerging Therapeutic Target

“…In the nervous system, neurotransmitters exert their effects through either individual GPCRs or a group of GPCRs known as neuromodulator receptor families. , The importance of GPCR signaling in maintaining proper brain function is evident from the fact that numerous neuropsychiatric disorders and neurological diseases arise from dysfunctional GPCRs. Consequently, the primary focus of drugs designed to treat nervous system disorders lies in targeting GPCRs …”