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Allosteric GPCRs Library

A sub-library of Enamine’s GPCR Library designed for discovery of novel allosteric ligands

17 385 compounds

Although modulating GPCRs with orthosteric selective drug candidates has numerous success stories, in many cases, allosteric GPCR ligands are more effective for these biological targets. The small molecule allosteric modulation of GPCRs can promote a conformational change in the receptor that often has no noticeable effects, but can have a strong impact on the signaling pathway in the presence of an orthosteric endogenous ligand. On the other hand, GPCRs actuated by intractable stimuli can be modulated allosterically, opening a new opportunity for these currently unassailable targets. Two allosteric GPCRs modulators that have been introduced in the clinic (Cinacalcet and Maraviroc) are excellent evidence of prospects of investigation in this area. Another benefit of these ligands is their relatively low molecular weight and hence higher potential for oral bioavailability, in contrast to most orthosteric ligands. Moreover, allosteric sites are generally less conserved enabling development of actives with greater subtype selectivity than drugs targeting the conserved binding site.

Enamine’s Allosteric GPCRs Library is a utile starting point for the drug discovery in the field of allosteric GPCR modulators.

Library design

Both ligand- and structure-based methods were used in design of the library. Ligand-based approach relied on using 3D pharmacophore search to the reference set of known ligands with high activity values (over 200 compounds from ChEMBL and BindingDB). The main emphasis has been done on allosteric modulators of class B GPCRs that are well established in drug discovery. Two pharmacophore models were created using the reference compounds sets and then validated with the training sets of actives and non-active ligands (Figure 1). Finally, over 6 200 small molecules were selected into Pharmacophore-based allosteric GPCR subset starting from Enamine MedChem set (710 K).

Fig. 1. Pharmacophore superposition of a reference active compound (in green) and a hit compound from the Library (in grey).

Structure-based approach was applied to human Glucagon receptor (GCGR) and human Corticotropin-releasing factor 1 receptor (CRF1R). The corresponding protein structures recorded in 5EE7 and 4K5Y PDB entries were optimized and used for the docking calculation with Glide (Schrödinger software). Compounds with at least 50% score-based efficacy as compared to the co-crystallized ligands were selected as hits and included in the targeted sets: h-GCGR set – 200 compounds; h-CRF1R set: 7 200 compounds (Figures 2 and 3).

Fig. 2. Binding mode of a hit (in red) obtained from the docking and the co-crystallized ligand (in green) of human Glucagon receptor.

Fig. 3. Superposition of a hit compound obtained after docking of CRF1R allosteric site with Enamine MedChem screening compounds (in green) and the co-crystallized ligand CP-376395 (in orange).

Examples of the molecules

Library Formats

Item
Catalog #
# of compounds
Amount
Plates and format

Item

1

Catalog #

AGL-Y-0

# of compounds

17 385

Amount

Minimum amount for 1 HTS

Plates and format

384-well plates (Matrix Cat. No 4312),
320 cpds per plate: first two and last two columns empty

Item

2

Catalog #

AGL-Z-4

# of compounds

17 385

Amount

4 µL of 2 mM
DMSO solution

Plates and format

1536-well plates (Matrix Cat. No 4312),
1280 cpds per plate: first four and last four columns empty

Item

3

Catalog #

AGL-Y-20

# of compounds

17 385

Amount

20 µL of 10 mM
DMSO solution

Plates and format

384 well plates (Matrix Cat. No 4312),
320 compounds / plate: first two andlast two columns empty

Item

4

Catalog #

AGL-Y-50

# of compounds

17 385

Amount

50 µL of 10 mM
solutions in DMSO

Plates and format

384 well plates (Matrix Cat. No 4312),
320 compounds / plate: first two andlast two columns empty

GPCR Library

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