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GPCR Libraries

Download General GPCR library SDF
Download Allosteric GPCRs Library SDF
Download Enamine & NQuiX Lipid GPCR Library SDF

G protein–coupled receptors (GPCRs) have been proven to be the most successful class of drugable targets in the human genome and remain the most attractive family of targets in the modern medicinal chemistry. Recent achievements of structural biology in GPCR research, including growing number of protein structures data, have opened new horizons in this area. Meanwhile accessible qualified chemistry support (e.g. high quality hit finding libraries, availability of advanced building blocks for scaffold hopping, efficient hit follow-up and hit-to-lead MedChem optimization) continue to play an important role for rapid and successful project performance.

Being the leading chemical supplier Enamine provides versatile opportunities for GPCR-based Drug Discovery encompassing Design of specific targeted Libraries, diverse off-the-shelf Scaffolds and Building Blocks as well as multiform Custom Chemistry Service.

General GPCR library

27 000 compounds deliverable as entire set or cherry-picked subsets

Enamine screening collection of over 2.2 M diverse small molecular is an excellent source for rapid hit finding in search for new GPCR ligands. A combined approach, including framework 2D-fingerprint similarity search, careful selection of GPCR privileged scaffolds and common moieties with extension of 3D pharmacophore searches, was used to design our General GPCRs targeted Library resulting in a unique set of 27 000 high quality small molecules.

All compounds have attractive drug-like structural features and molecular profile with appropriative chemical novelty values. The following molecular restrictions have been used in construction of the Library:

MW 250 … 500, ClogP 2 … 4, TPSA < 150 Å2, RotBonds 0 … 8, Hb Donor < 4, Hb Acceptors < 10.

MedChem refinement and PAINS exclusion filters have finalized library design.

The main emphasis in the library design was made on new Chemotypes and new Molecular Frameworks

Examples of Enamine GPCR library compounds having pharmacophore  similarity to Ambrisentan (left) and bearing scaffolds that are bioisosteric to the  spiro-piperidine-indane privileged fragment (right).

Figure 1. Examples of Enamine GPCR library compounds having pharmacophore similarity to Ambrisentan (left) and bearing scaffolds that are bioisosteric to the spiro-piperidine-indane privileged fragment (right).

Examples of compounds

Figure 2. Novel sp-enriched scaffolds specifically designed and synthesized as promising core for new GPCR ligands

 

Allosteric GPCRs Library

17 385 compounds

We are delighted to offer a library of carefully selected compound sets as prospective allosteric GPCR modulators:

  • General Library comprises over 13 000 off-the-shelf available compounds
  • Pharmacophore based allosteric GPCR set: 6 200 compounds

The library is a utile starting point for the drug discovery in the field of allosteric GPCR modulators.

In spite of the proven success of GPCRs as drug targets, many intense efforts to develop orthosteric selective drug candidates for GPCRs have failed. Thus, numerous studies to discover selective allosteric GPCR modulators are of great interest in this area. The small molecule allosteric modulation of GPCRs can promote a conformational change in the receptor that often alone produces no noticeable downstream effects, but in the presence of an orthosteric ligand can significantly increase efficacy and have a strong impact on changing of signaling pathway.

Another advantage is that undrugable GPCRs that are actuated by intractable stimuli can be modulated allosterically by synthetically accessible small molecules, opening a new opportunity to target unassailable. Two allosteric GPCRs modulators that have been introduced in the clinic (Cinacalcet and Maraviroc) are excellent evidence of prospects of investigation in this area.

Additionally, benefit of development of such modulators is that allosteric site can be targeted with low molecular weight ligands that have high potential for oral bioavailability in contrast to structural features of most orthosteric ligands. Besides, allosteric sites are generally less conserved enabling development of actives with greater subtype selectivity than drugs targeting the conserved binding site.

Pharmacophore based Library was created using 3D Pharmacophore search to the reference set of known ligands with high activity values (>200 compounds from ChEMBL, Bindingdb).  The main emphasis has been done on allosteric modulators of class B GPCRs that are well established in drug development. Two pharmacophore models were created basing on the reference compounds sets and then validated with the training sets of actives and non-active ligands. Finally, over 6 000 small molecules from Enamine MedChem subset (710 K) were included in the Library.

Figure 3. Pharmacophore superposition of a reference active compound (carbons in green lines) and a hit compound from the Library (in stick representation).

Figure 4. Examples of the molecules from Pharmacophore based allosteric GPCR ibrary.

Targeted Sets of GPCR allosteric modulators:

  • h-Glucagon receptor (GCGR) targeted set: 200 compounds;
  • h-Corticotropin-releasing factor 1 receptor (CRF1R) targeted set: 7 200 compounds.

The sets of small molecules were created using in silico screening against promising targets with reported structural data. The docking calculations were carried out on h-Glucagon receptor (GCGR) and h-Corticotropin-releasing factor 1 receptor (CRF1R) validated models. Corresponding protein structures recorded in 5EE7 and 4K5Y PDB entry were optimized and used for the docking calculation with Glide (Schrödinger software). Compounds with scores of at least 50% efficacy of the scoring results obtained for co-crystallized ligands were selected as hits and included in the targeted sets.

Figure 5. Example of the binding mode of hit (in red) obtained from the docking and co-crystallized ligand (in green) of h-Glucagon receptor.

Figure 6. Superposition of a hit (colored in green) compound and co-crystallized ligand CP-376395 (in orange stick representation) obtained after docking of CRF1R allosteric site with Enamine MedChem compounds subset.

 

Enamine & NQuiX Lipid GPCR Library

7 500 compounds

Enamine Lipid GPCRs focused Library has been designed in collaboration with NQuiX. Over 7 500 compounds have been selected from off-the-shelf collection and specifically synthesized for this project from Enamine REAL screening Collection. They target the family of 8 EDG receptors (S1P1-5 and LPA1-3). The compounds may also be appropriate for screening at GPR3, GPR6 and GPR12 orphan receptors given some TM bundle binding site similarity and/or GPR23, GPR92 and P2Y5 given their more recent classification as additional, albeit distinct, LPA receptors.

The compounds have been selected using a combination of ligand-based methods including chemical fingerprints, 2D pharmacophores and 3D shape/feature matches. They represent a combination of compounds for expanding SAR around known chemotypes and scaffold hops seeking novelty. The current set of compounds covers the non-acidic classes of ligand, with acidic compounds being designed via a different procedure and offered separately.

Figure 7. General scheme of dedicated design of compound structures included in the Library.

Examples of non-acidic  compounds in the Lipid GPCRs Library.

Figure 8. Examples of non-acidic compounds in the Lipid GPCRs Library. 

The total number of unique compounds with activity (collected across 73 papers) is 1 393 of which 870 are acidic and 523 are non-acidic. The non-acidic ligands formed the basis for the library design via a combination of ligand-based selection methods.

 Activity distribution of the training active compound set

Figure 9. Activity distribution of the training active compound set.



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