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, which are associated with the vast biological functions mediated by GPCRs [1]. More than ⅓ of all marketed drugs act through modulation of GPCR functions and up to 70 % of novel therapeutics in development target known GPCRs.

Life Chemicals has designed a novel Screening Library of GPCR targeting compounds intended for screening in GPCR-related drug discovery projects. The applied receptor based approach involved application of 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).

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. The reference set of compounds selected for screening validation contained known and proven inhibitors of GPCRs derived from the ChEMBL database. Glide Docking (Schrödinger) and Unity modeling (SYBYL-X) protocols were applied for docking and screening procedures (Fig. 1). Docking of the reference set has been done to provide full information about possible conformations of the active ligands and interaction types one can expect as a result of a HTS procedure.

Over 8,500 drug-like screeningcompounds with predicted GPCR antagonist activity against 16 GPCR targets were selected. Hit ranking of the potential GPCR ligands was based on score values obtained from docking of the reference set.

Binding mode (by flexible docking) of Life Chemicals compounds in the 5HT-2B receptor binding site considering water molecules orientation. A. Compound F0191-4611 B. Compound F3124-0549.

Fig1. Binding mode (by flexible docking) of Life Chemicals compounds in the 5HT-2B receptor binding site considering water molecules orientation. A. Compound F0191-4611 B. Compound F3124-0549.

The list of GPCR target proteins  and the corresponding number of compounds obtained by means of HTS:

Adenosine receptor

  • A2A 197 compounds
  • A2B* 1054 compounds
  • A3* 149 compounds

Chemokine receptor

  • CXCR4 805 compounds
  • CCR5* 367 compounds

Histamine receptor

  • H1    925 compounds
  • H3* 149 compounds
  • H4* 1,131 compounds

Opioid receptor

  • Delta-type 825 compounds
  • Kappa-type 696 compounds
  • Mu-type     669 compounds
  • Dopamine D3 receptor 1,911 compounds
  • GABA receptor subunit 295 compounds
  • Muscarinic acethylcholine receptor type 21,126 compounds
  • Sphingosine 1-phosphate receptor 822 compounds
  • Serotonine receptors (type 5HT1B) 650 compounds

*homology modelling approach

References:

  1. Zhou J, Wild C. GPCR Drug Discovery: Emerging Targets, Novel Approaches and Future Trends. Curr Top Med Chem. 2019;19(16):1363-1364. doi:10.2174/156802661916190828093500 
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