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GPCR Targeted Library by Receptor-based Approach

G-protein coupled receptors (GPCRs) are a class of seven-transmembrane proteins that play crucial roles in physiological responses to a variety of stimuli, such as small molecules, ions, macromolecules, peptides, and other proteins [1]. GPCRs play several critical physiological functions in the body, such as the regulation of behavior and mood, the regulation of immune system activity, the growth and metastasis of cancerous tumors, and the transmission of signals through the autonomic nervous system. These diverse functions make GPCRs promising drug targets: up-to-date, around one-third of all existing drugs, are aimed at modulating GPCR functions, and 70 % of drugs under development also target GPCRs [2].

With the above considerations in mind, our cheminformatics team has designed a novel Screening Library of over 9,600 GPCR-targeting screening compounds to be of great practical use for screening in GPCR-related drug discovery projects. The applied receptor-based approach involved several computational methods, such as homology modeling, reference compounds set selection and analysis, molecular dynamics, molecular docking, and in silico version of high-throughput screening (HTS).

The compound selection can be customized based on your requirements, cherry picking is available.

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G-protein-coupled-receptor signaling pathway [3].

Figure 1. G-protein-coupled-receptor signaling pathway [3].

Compound selection

The reference set of compounds selected for screening validation contained reported GPCR inhibitors derived from the ChEMBL database.

Each GPCR target (see the list of targets below) was prepared and optimized with Schrödinger software. Some individual protein structures were further relaxed with molecular dynamics simulation in GROMACS.

Glide Docking (Schrödinger) and Unity modeling (SYBYL-X) protocols were applied for docking and screening procedures against the HTS Compound Collection (Fig. 1). Docking of the reference set has been performed to provide full information about possible conformations of the active ligands and interaction types one can expect as a result of the virtual HTS procedure.

As a result, over 8,100 drug-like screeningcompounds with predicted GPCR antagonist activity against 16 GPCR targets were selected. The list of GPCR target proteins employed in the in silico screening is given below:

  • Adenosine receptors A2A, A2B*, A3*
  • Chemokine receptors CXCR4, CCR5*
  • Histamine receptors H1, H3*, H4*
  • Opioid receptors delta (DOP), kappa (KOP), mu (MOP)
  • Dopamine D3 receptor
  • GABA receptor subunit
  • Muscarinic acetylcholine receptor type
  • Sphingosine 1-phosphate receptor
  • Serotonine receptors (type 5HT1B)

*homology modeling approach

Additionally, over 1,500 structurally-diverse screening molecules picked out by phase ligand screening based on the pharmacophore hypothesis were added to this Targeted Screening Library:

Adenosine receptor A2a (A2AAR)

Adenosine A2A receptor (A2AAR), also known as ADORA2A, belongs to the G-protein-coupled receptor superfamily (GPCR) [4]. This receptor is a transmembrane protein in the cell membrane of many cell types of the body and is involved in the regulation of various functions, which makes it a potential target for the treatment of several pathologies [5], such as Parkinson's disease [6], cancer [7], and cardiovascular diseases [8].

Key features:

  • Method: Phase Ligand Screening
  • X-Ray data used: 4EIY
  • Filters used: PAINS, toxic, reactive
  • Number of compounds selected: 875

Pharmacophore hypothesis in the A2AAR binding site

Figure 3. Pharmacophore hypothesis in the A2AAR binding site.

Calcitonin gene-related peptide type 1 receptor (CGRP)

The calcitonin gene-related peptide type 1 receptor (CGRP type 1 receptor) belongs to the G-protein-coupled receptor (GPCR) superfamily. This receptor consists of the calcitonin receptor (CLR, class B GPCR) and receptor activity modifying protein type 1 (RAMP1) [9]. Together with the receptor activity modifying protein type 3 (RAMP3), the CGRP type 1 receptor is an adrenomedullin receptor. CGRP is a multi-pass membrane protein [10]. The level of CGRP in the cell is shown to increase during a migraine attack, thus making this protein an important target in pain therapy [1]. It has also been found that CGRP, together with RAMP1, is involved in bone formation after fractures, however, overexpression of CGRP is commonly observed in pathological conditions, including metastatic cancer lesions in bone and fractures that are slow to heal or remain practically unhealable, leading to persistent chronic pain [11].

Key features:

  • Method: Phase Ligand Screening
  • X-Ray data used: 6ZIS
  • Filters used: PAINS, toxic, reactive
  • Number of compounds selected: 693

Pharmacophore hypothesis in the GPCR binding site.

Figure 4. Pharmacophore hypothesis in the GPCR binding site.


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  2. Slosky LM, Caron MG, Barak LS. Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery. Trends Pharmacol Sci. 2021;42(4):283-299. doi:10.1016/
  4. Huang SK, Almurad O, Pejana RJ, et al. Allosteric modulation of the adenosine A2A receptor by cholesterol. Elife. 2022;11:e73901. Published 2022 Jan 5. doi:10.7554/eLife.73901
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  7. Sun C, Wang B, Hao S. Adenosine-A2A Receptor Pathway in Cancer Immunotherapy. Front Immunol. 2022;13:837230. Published 2022 Mar 21. doi:10.3389/fimmu.2022.837230
  8. Al-Attraqchi OHA, Attimarad M, Venugopala KN, Nair A, Al-Attraqchi NHA. Adenosine A2A Receptor as a Potential Drug Target - Current Status and Future Perspectives. Curr Pharm Des. 2019;25(25):2716-2740. doi:10.2174/1381612825666190716113444
  9. Rujan RM, Reynolds CA. Calcitonin Gene-Related Peptide Antagonists and Therapeutic Antibodies. Handb Exp Pharmacol. 2019;255:169-192. doi:10.1007/164_2018_173
  10. Mackie DI, Al Mutairi F, Davis RB, et al. hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia. J Exp Med. 2018;215(9):2339-2353. doi:10.1084/jem.20180528
  11. Xu J, Wang J, Chen X, Li Y, Mi J, Qin L. The Effects of Calcitonin Gene-Related Peptide on Bone Homeostasis and Regeneration. Curr Osteoporos Rep. 2020;18(6):621-632. doi:10.1007/s11914-020-00624-0
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