A review on current and future challenges in gpcr drug discovery

Manoj Kumar Rekala

Rekala Manoj Kumar Priyadarshini Institute of Pharmaceutical Education and Research, 5th Mile, Pulladigunta, Guntur-522017, Andhra Pradesh, India.

Abstract

G-protein-coupled receptors (GPCRs) are essential components in cell signaling, influencing a wide array of physiological processes. They are the largest and most diverse family of cell surface receptors, and over the years, significant progress has been made in understanding their structure and function. Since the cloning of the first GPCR in 1986, research has unveiled their critical role as drug targets, leading to their status as the most successful receptor class for approved therapeutic agents. In drug discovery, insights into receptor dynamics-ranging from agonist to antagonist effects—are fundamental to developing effective therapies. Advances in structural biology and molecular simulations have provided a deeper understanding of GPCR activation mechanisms, which are essential in designing drugs that can either enhance or inhibit receptor activity. Allosteric sites, which provide alternative pathways for drug modulation, are emerging as promising targets for future drug design. Recent studies have focused on small-molecule allosteric modulators, revealing how they interact with receptors at the molecular level to produce therapeutic outcomes. The growing knowledge of GPCR mechanisms is poised to advance the development of innovative therapies, with new technologies and methodologies enabling the creation of more selective and effective drugs. Future research will continue to explore GPCRs' complex signaling networks, providing critical insights into their potential for treating a variety of conditions.

Keywords: G-Protein Coupled Receptors (GPCR), Signature discovery, Drug discovery Small molecule Biomarker Allosteric drug, biased drug; bitopic ligand, bivalent ligand, heteromer-selective drug

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