Rational drug design targeting G-protein-coupled receptors: ligand search and screening (review)

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Abstract

G protein-coupled receptors (GPCRs) are transmembrane proteins that participate in most physiological processes and serve as key pharmacological targets. Recent advances in structural biology of GPCRs have enabled the development of drugs based on structure (Structure Based Drug Design, SBDD). SBDD utilizes information about the receptor– ligand complex to search for suitable compounds, expanding the chemical space of search without the need for experimental screening. In our review we include a description of Structural-base Virtual Screening (SBVS) of ligands to GPCRs and a description of methods for functional testing of selected potential drug compounds. We also discuss recent advances in the development of SBDD approaches applicable to GPCRs and highlight successful examples of their use.

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About the authors

А. P. Luginina

Moscow Institute of Physics and Technology (NIU)

Author for correspondence.
Email: borshchevskiy.vi@phystech.edu
Russian Federation, 141701, Dolgoprudny, Moscow Region

A. N. Khnykin

Moscow Institute of Physics and Technology (NIU)

Email: borshchevskiy.vi@phystech.edu
Russian Federation, 141701, Dolgoprudny, Moscow Region

P. А. Khorn

Moscow Institute of Physics and Technology (NIU)

Email: borshchevskiy.vi@phystech.edu
Russian Federation, 141701, Dolgoprudny, Moscow Region

О. V. Moiseeva

Moscow Institute of Physics and Technology (NIU); G. K. Skryabin Institute of Biochemistry and Physiology of Microorganisms, Russian Academy of Sciences

Email: borshchevskiy.vi@phystech.edu
Russian Federation, 141701, Dolgoprudny, Moscow Region; 142290, Pushchino, Moscow Region

N. A. Safronova

Moscow Institute of Physics and Technology (NIU)

Email: borshchevskiy.vi@phystech.edu
Russian Federation, 141701, Dolgoprudny, Moscow Region

V. A. Pospelov

Moscow Institute of Physics and Technology (NIU)

Email: borshchevskiy.vi@phystech.edu
Russian Federation, 141701, Dolgoprudny, Moscow Region

D. E. Dashevskii

Moscow Institute of Physics and Technology (NIU)

Email: borshchevskiy.vi@phystech.edu
Russian Federation, 141701, Dolgoprudny, Moscow Region

A. S. Belousov

Moscow Institute of Physics and Technology (NIU)

Email: borshchevskiy.vi@phystech.edu
Russian Federation, 141701, Dolgoprudny, Moscow Region

I. V. Borshchevskiy

Moscow Institute of Physics and Technology (NIU); Joint Institute for Nuclear Research

Email: borshchevskiy.vi@phystech.edu
Russian Federation, 141701, Dolgoprudny, Moscow Region; 141980, Dubna, Moscow Region

A. V. Mishin

Moscow Institute of Physics and Technology (NIU)

Email: mishinalexey@phystech.edu
Russian Federation, 141701, Dolgoprudny, Moscow Region

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2. Fig. 1. The general principle of GPCR signal transmission: a selective ligand, approaching from the extracellular side, activates a receptor, which, undergoing conformational changes, activates a G-protein heterotrimer consisting of α-, β- and γ-subunits. The activated receptor, which interacts with the heterotrimer as a whole, initiates its dissociation, catalyzing the exchange of GDP for GTP in the nucleotide center of the Ga subunit, which determines the further cascade of reactions. For example, Ga12/13 starts the Rac/Rho path of small GTPases; Gaas stimulate, and Gai/o inhibit adenylate cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP); Gaq stimulates phospholipase C-β (PLC-β), cleaving off phosphatidylinositol biphosphate (its isoform PI-3,5-P2) inositol triphosphate (IP3), an increase in the concentration of which leads to release of intracellular calcium. Secondary messengers include an appropriate cellular response. Gßy subunits also trigger a number of signaling pathways, for example, by interacting with ion channels, lipid kinases (phosphoinositide-3-kinase-γ, PI3Ky) and phospholipases (PLC-β). With prolonged activation, the receptor can be phosphorylated, for example, by GPCR kinase (GRK), which leads to binding to the arrestin protein (Arr), which terminates the G-protein-associated signaling pathway [5]

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3. Fig. 2. Methods for analyzing intracellular GPCR signaling used for screening compound libraries. The sun indicates a detectable signal of chemiluminescence, fluorescence caused by the interaction of molecules with sensors, the assembly of a fluorescent protein or resonant energy transfer occurring when macromolecules approach

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