Drug Repurposing on G Protein-Coupled Receptors Using a Computational Profiling Approach
Alessandra de Felice, Simone Aureli, Vittorio Limongelli
Abstract
G protein-coupled receptors (GPCRs) are the largest human membrane receptor family regulating a wide range of cell signaling. For this reason, GPCRs are highly desirable drug targets, with approximately 40% of prescribed medicines targeting a member of this receptor family. The structural homology of GPCRs and the broad spectrum of applications of GPCR-acting drugs suggest an investigation of the cross-activity of a drug toward different GPCR receptors with the aim of rationalizing drug side effects, designing more selective and less toxic compounds, and possibly proposing off-label therapeutic applications. Herein, we present an original in silico approach named “Computational Profiling for GPCRs” (CPG), which is able to represent, in a one-dimensional (1D) string, the physico-chemical properties of a ligand–GPCR binding interaction and, through a tailored alignment algorithm, repurpose the ligand for a different GPCR. We show three case studies where docking calculations and pharmacological data confirm the drug repurposing findings obtained through CPG on 5-hydroxytryptamine receptor 2B, beta-2 adrenergic receptor, and M2 muscarinic acetylcholine receptor. The CPG code is released as a user-friendly graphical user interface with numerous options that make CPG a powerful tool to assist the drug design of GPCR ligands.