REVIEW: Rational Design of Drugs Targeting G-Protein-Coupled Receptors: A Structural Biology Perspective

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Polina A. Khorn¹, Aleksandra P. Luginina¹, Vladimir A. Pospelov¹, Dmitrii E. Dashevsky¹, Andrey N. Khnykin¹, Olga V. Moiseeva^1,2, Nadezhda A. Safronova¹, Anatolii S. Belousov¹, Alexey V. Mishin^1,a*, and Valentin I. Borshchevsky^1,3,b*

¹Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Moscow Region, Russia

²Scryabin Institute of Biochemistry and Physiology of Microorganisms, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia

³Joint Institute for Nuclear Research, Frank Laboratory of Neutron Physics, 141980 Dubna, Moscow Region, Russia

Received September 21, 2023; Revised February 22, 2024; Accepted February 29, 2024

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G protein-coupled receptors (GPCRs) play a key role in the transduction of extracellular signals to cells and regulation of many biological processes, which makes these membrane proteins one of the most important targets for pharmacological agents. A significant increase in the number of resolved atomic structures of GPCRs has opened the possibility of developing pharmaceuticals targeting these receptors via structure-based drug design (SBDD). SBDD employs information on the structure of receptor–ligand complexes to search for selective ligands without the need for an extensive high-throughput experimental ligand screening and can significantly expand the chemical space for ligand search. In this review, we describe the process of deciphering GPCR structures using X-ray diffraction analysis and cryoelectron microscopy as an important stage in the rational design of drugs targeting this receptor class. Our main goal was to present modern developments and key features of experimental methods used in SBDD of GPCR-targeting agents to a wide range of specialists.

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KEY WORDS: drug development, GPCR, macromolecular crystallography, cryo-electron microscopy, structure-based drug design

DOI: 10.1134/S0006297924040138

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