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.
Highlights
G protein-coupled receptors (GPCRs) are integral membrane proteins involved in the transduction of a wide range of signals from outside the cell to the cellular interior
Employing Computational Profiling for GPCRs” (CPG), we found that the lisuride–5HT2B and alprenolol–ADRB2 complexes show a 10 Digit Profile” (10DP) alignment score of 0.54, higher than the threshold value 0.5 (Table 1), suggesting that lisuride and alprenolol could be repurposed as novel ligands for their reciprocal GPCRs
A profiling methodology called Computational Profiling GPCRs (CPG) has been proposed here, which combines the primary structure of a GPCR with three-dimensional (3D) information when the receptor is complexed with a ligand, making the extraction of valuable data relating to the ligand– GPCR binding affinity possible
Summary
G protein-coupled receptors (GPCRs) are integral membrane proteins involved in the transduction of a wide range of signals from outside the cell to the cellular interior. They represent the largest and most pharmacologically relevant protein family—∼4% of the protein-coding genome (Fredriksson et al, 2003; Zhang et al, 2006). Some GPCRs have an additional α-helix (H8) at the C-terminal (Yeagle and Albert, 2007). GPCRs interact with the G-protein heterotrimer complex (Gαβγ) through a process allosterically modulated by ligand-induced conformational changes that activate a specific signal cascade based on the type of the interacting Gα-protein (Gs, Gi, Go, Gq/11, G12/13)
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