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

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Abstract

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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Abbreviations

BRIL:

thermostabilized apocytochrome b562

CCD:

coupled charge device

cryo-EM:

cryo-electron microscopy

Fab fragment:

antigen-binding antibody fragment

GPCR:

G protein-coupled receptor

ICL3:

intracellular loop 3

LCP:

lipidic cubic phase

MMS:

membrane modeling system

MX:

macromolecular crystallography

SR:

synchrotron radiation

SBDD:

structure based drug design

SFX:

serial femtosecond X-ray crystallography

SWSX:

small-wedge synchrotron crystallography

XFEL:

X-ray free electron laser

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Funding

This work was supported by the Russian Science Foundation (project no. 22-74-00024, https://rscf.ru/project/22-74-00024/ [in Russian]; section “Preparation of GPCRs for crystallization”; project no. 22-74-10036, https://rscf.ru/project/22-74-10036/ [in Russian]; “Cryo-electron microscopy” section) and by the Ministry of Science and Higher Education (grant agreement 075-03-2024-117, project FSMG-2024-0012; “GPCR crystallization” section; grant agreement 075-15-2021-1354, MX methods in GPCR studies).

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Authors and Affiliations

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

    Polina A. Khorn, Aleksandra P. Luginina, Vladimir A. Pospelov, Dmitrii E. Dashevsky, Andrey N. Khnykin, Olga V. Moiseeva, Nadezhda A. Safronova, Anatolii S. Belousov, Alexey V. Mishin & Valentin I. Borshchevsky

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

    Olga V. Moiseeva

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

    Valentin I. Borshchevsky

Authors
  1. Polina A. Khorn
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  2. Aleksandra P. Luginina
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  3. Vladimir A. Pospelov
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  4. Dmitrii E. Dashevsky
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  5. Andrey N. Khnykin
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  6. Olga V. Moiseeva
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  7. Nadezhda A. Safronova
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  8. Anatolii S. Belousov
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  9. Alexey V. Mishin
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  10. Valentin I. Borshchevsky
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Contributions

A.M. and N.S. wrote the Introduction; V.P., A.B., P.Kh., and V.B. wrote the “Protein crystallography” section; A.L. and D.D. wrote the Cryo-EM section; A.L., P.Kh., V.P., D.D., A.Kh., and A.B. prepared the figures; A.M., A.L., O.M. edited the manuscript; P.Kh., A.L., A.M., and V.B. proposed the concept of the article.

Corresponding authors

Correspondence to Alexey V. Mishin or Valentin I. Borshchevsky.

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Khorn, P.A., Luginina, A.P., Pospelov, V.A. et al. Rational Design of Drugs Targeting G-Protein-Coupled Receptors: A Structural Biology Perspective. Biochemistry Moscow 89, 747–764 (2024). https://doi.org/10.1134/S0006297924040138

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  • DOI: https://doi.org/10.1134/S0006297924040138

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