Discovery of GPCR ligands for probing signal transduction pathways

Abstract

G protein-coupled receptors (GPCRs) are seven integral transmembrane proteins that are the primary targets of almost 30% of approved drugs and continue to represent a major focus of pharmaceutical research. All of GPCR targeted medicines were discovered by classical medicinal chemistry approaches. After the first GPCR crystal structures were determined, the docking screens using these structures lead to discovery of more novel and potent ligands. There are over 360 pharmaceutically relevant GPCRs in the human genome and to date about only 30 of structures have been determined. For these reasons, computational techniques such as homology modeling and molecular dynamics simulations have proven their usefulness to explore the structure and function of GPCRs. Furthermore, structure-based drug design and in silico screening (High Throughput Docking) are still the most common computational procedures in GPCRs drug discovery. Moreover, ligand-based methods such as three-dimensional quantitative structure-selectivity relationships, are the ideal molecular modeling approaches to rationalize the activity of tested GPCR ligands and identify novel GPCR ligands. In this review, we discuss the most recent advances for the computational approaches to effectively guide selectivity and affinity of ligands. We also describe novel approaches in medicinal chemistry, such as the development of biased agonists, allosteric modulators, and bivalent ligands for class A GPCRs. Furthermore, we highlight some knockout mice models in discovering biased signaling selectivity.

Keywords: G protein-coupled receptors; GPCR; allosteric modulators; biased agonists; biased signaling; bivalent ligands; high throughput docking; homology modeling.

FIGURE 1

Structure of rhodopsin. (A) Crystal structure of bovine rhodopsin covalently linked with retinal adapted from PDB file 1F88. (B) Snake-like diagram for the bovine rhodopsin highlighting extracellular (EC) and intracellular (IC) loops.

FIGURE 2

Functional responses of allosteric modulators. Positive and negative allosteric modulators (positive allosteric modulators and negative allosteric modulators) may modulate the affinity and/or the efficacy of orthosteric agonists.

FIGURE 3

Selected examples of mGluR5 allosteric ligands illustrating how a minimal structural variation can deeply affect the allosteric profile.

FIGURE 4

Structure of approved allosteric modulators.

FIGURE 5

Binding mode of monovalent, bitopic orthosteric/allosteric, and bivalent orthosteric/allosteric ligands of GPCRs.

FIGURE 6

Structure of monovalent drugs acting on GPCR dimers.

FIGURE 7

Structure of bivalent ligands that display in vivo pharmacological activities.

FIGURE 8

Signaling of biased agonists. G-protein biased agonists preferentially activate G-protein signaling. β-arrestin biased agonists activate β-arrestin signaling, and mutation mediated biased signaling may modify the G protein coupling.