Estrogen Receptor Library

Designed to effectively target the receptor and block estrogen release

8 320 compounds

Breast cancer remains one of the major health problems among the women’s population. This disease frightens millions of women around the world. The tremendous efforts of researchers and drug developers in this field have made significant progress in treatment and early diagnostics. Breast cancer is often fueled by hormones and most commonly uses estrogen to grow. Treatment with anti-estrogen therapy can effectively block the growth of the cancer cells. Thus, Estrogen Receptor (ER) remains the most important target for the development of new effective drugs against breast cancer.

We combined different approaches in the design of ER focused library to bring the most promising and convenient for follow-up starting points in your screening campaign. The library has been carefully reviewed in the context of MedChem tractability and intrinsic high diversity. Additionally, compounds were reviewed for sufficient solubility and stability in DMSO solution to ensure the high quality of the library.

The Estrogen Receptor library is available for delivery in different pre-plated formats.

Typical Formats

Catalog No.
Compounds
Amount
Format
Price

Catalog No.

ERL-8320-0-Z-10

Compounds

8 320
7 plates

Amount

≤ 150 nL of 10 mM of DMSO solutions

Plates and formats

1536-well echo microplates, first and last four columns empty, 1280 compounds per plate

Price

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Catalog No.

ERL-8320-10-Y-10

Compounds

8 320
26 plates

Amount

10 µL of 10 mM DMSO solutions

Plates and formats

384-well echo LDV plates, 1, 2 and 23, 24 columns empty, 320 compounds per plate

Price

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Catalog No.

ERL-8320-50-X-10

Compounds

8 320
157 plates

Amount

50µL of 10 mM DMSO solutions

Plates and formats

96-well Greiner bio-one plates, 1 and 12 columns empty, 80 compounds per plate

Price

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Catalog No.

ERL-8320

Compounds

8 320

Amount

Custom

Plates and formats

Any custom format

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Estrogen Receptor Library

Library code: ERL-8320

8 320 compounds

Library design

The database of activities related to SERMs (Selective Estrogen Receptor Modulators) was collected from the public domain (ChEMBL and Reaxys) and analyzed by the activity range. In total, about 15k activities were found, analyzed, and then separated by chemotypes. The most interesting from medchem prospective scaffolds were used for substructure searches, while the most active molecules were assembled into a validation set for in silico models – 3D pharmacophore and docking.

In addition, all available RE structures in PDB were combined and analyzed. Over 200 co-crystallized ligands with ER-alpha were extracted and superimposed to identify the most important interaction points and common structural motifs.

 

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).

About 15 distinct pharmacophores were identified with the four most common interaction maps selected for the in silico models:

  • Estrogen receptor alpha 7 clusters based on PDB ID: 1sj0, 2iog, 2qxm, 3os8, 5aau, 5dwi, 5krj.
  • Estrogen receptor beta 5 clusters based on PDB ID: 1nde, 1qkm, 2fsz, 2giu2yly.

 

Three 3D-pharmacophore models with exclusion volume were built, validated, and then used for the search of potential new ER ligands. As a result, over 10k compounds were identified as potential hits for ER-alpha, and 7k+ potentially active compounds were identified for ER-beta. The final library of potential estrogen receptor modulators passed through a manual review of predicted binding poses and was filtered using extended MedChem filters.

Examples of the pharmacophore models with reference molecules and predicted hits

 

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

GPCR Library

Covalent Enantiomeric Pairs Library

Enantiomeric pairs of covalent electrophilic fragments

960 compounds

Covalent chemical probes have become a valuable tool in drug discovery within the last few years. New technologies and development of fast mass spectrometric screening and imaging open a new horizon for proteome-wide screening and proteomics discoveries. The impressive number of successful applications brought aspiration to the discovery and synthesis of new covalent probes. Previously developed by Cravatt research group mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs makes this field especially attractive for further investigations.

To support further research of the stereoselective interaction of proteins with chiral covalent small-molecules we designed and specially synthesized two sets of fragments with the most robust covalent warheads – acrylamides and chloroacetamides.

Typical Formats

Catalog No.
Compounds
Amount
Format
Price

Catalog No.

EPL-960-10-Y-100

Compounds

960
3 plates

Amount

10 µL of 100 mM DMSO solutions

Plates and formats

384-well echo qualified LDV microplates, 1,2 and 23, 24 columns empty, 320 compounds per plate

Price

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Catalog No.

EPL-960-25-Y-20

Compounds

960
3 plates

Amount

25 µL of 20 mM DMSO solutions

Plates and formats

384-well microplates, Greiner bio-one, 1, 2 and 23, 24 columns empty, 320 compounds per plate

Price

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Catalog No.

EPL-960-50-X-20

Compounds

960
12 plates

Amount

50 µL of 20 mM DMSO solutions

Plates and formats

96-well plates, 2D-barcoded microtubes with first and last columns empty, 80 compounds per plate

Price

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Catalog No.

EPL-960

Compounds

960

Amount

Custom

Plates and formats

Any custom format

Price

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Covalent Enantiomeric Pairs Library

Library code: EPL-960

Version: 3 March 2024

960 compounds
at 100 mM in DMSO

Enantiomeric Pairs Acrylamide sublibrary

640 compounds
at 100 mM in DMSO

Enantiomeric Pairs Chloracetamide sublibrary

320 compounds
at 100 mM in DMSO

More than 6000 chiral building blocks with enantiomeric excess (ee) purity of 90%+ were analyzed and triaged for further synthesis of covalent binder pairs. The resulting set of over 2000 of the most diverse novel covalent modifiers has been synthesized. The enantiomeric purity of the corresponding enantiomeric pairs was analyzed by chiral chromatography. Compounds that passed rigorous QC and selection based on the diversity and Ro3 criteria were assembled into the Covalent Enantiomeric Pairs Library.

Key features

  • Stereoselective interaction of target with enantiomeric covalent binder provides evidence of ligand-protein interaction
  • Information about “correct” stereochemistry of hit on early stage
  • Most common and well-validated warheads

 

Enatiomeric Pairs Fragment Library is plated at 100 mM concentration and is available for fast supply in different formats. The Library consists of two sublibraries, which can be acquired separately.

CNS Fragment Library

CNS-friendly molecules capable of BBB penetration

1 280 pre-plated fragments

Despite extensive research efforts, CNS drug discovery remains among the most challenging fields for drug developers. Factors such as heightened pollution, an aging population, and the impact of the global pandemic have collectively contributed to the increase of various CNS disorders. Regardless of great progress in diagnostics which is still limited in access, this field remains in desperate need of new effective, and safe treatments for most serious and frightening disorders.

To help scientists at very early stages, we designed a specialized library of small fragments intended to bring convenient starting points that can quickly progress to potent CNS lead series. Analyzing all existing CNS drugs and drug candidates we created special selection criteria and structural patterns to identify potentially active molecules. This algorithm has been applied to Enamine’s Fragment Collection to reflect the most promising structures. The library was finalized with cluster-based diversity selections and manual review.

Typical Formats

Catalog No.
Compounds
Amount
Format
Price

Catalog No.

CNSF-1280-X-50-100

Compounds

1 280
16 plates

Amount

50 µL of 100 mM DMSO solutions

Plates and formats

96-well plates, first and last columns empty, 2D-barcoded vials (optional), 80 compounds per plate

Price

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Catalog No.

CNSF-1280-Y-10-100

Compounds

1 280
4 plates

Amount

10 µL of 100 mM DMSO solutions

Plates and formats

384-well plates, 1, 2 & 23, 24 columns empty; 320 compounds per plate

Price

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Catalog No.

CNSF-1280-Y-25-100

Compounds

1 280
4 plates

Amount

25 µL of 100 mM DMSO solutions

Plates and formats

384-well plates, 1, 2 & 23, 24 columns empty; 320 compounds per plate

Price

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Catalog No.

CNSF-1280

Compounds

1 280

Amount

Custom

Plates and formats

Any custom format

Price

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CNS Fragment Library

Library code: CNSF-1

Version: 25 October 2023

1 280 compounds

Key features

 

  • High CNS scores: CNS MPO > 4.0 & QikProp CNS > 0
  • Preferred scaffolds and chemotypes
  • Rigorous MedChem filters and structure review

 

Parameter Range Parameter Range
MW < 200 RotBonds ≤ 3
ClogP < 3.0 ClogP-(N+O) > -2.0
PSA ≤ 60 Å2 Fsp3 0.15 ... 0.8
Hb Donor ≤ 3 Ring count ≤ 3
Hb Acceptor ≤ 5 Basic Nitrogen ≤ 2
Total H-bonding < 8 S, Cl atoms ≤ 2
Carboxylic acids ≤ 1, no more than 10% of CA
No more than 2 amide bonds, 87% with one amide bond
No quaternary Nitrogen, no NO2, Br, I, P

Novelty

Compounds included into CNS focused Library were selected from all three screening collections - HTS, Advanced and Premium. Preference was given to the compounds synthesized within the last 4 years, based on innovative scaffolds and with use of advanced building blocks to enhance the novelty value of the library.

Molecular properties

Сovalent MiniFrags

Covalent Heterocyclic Fragment Library for identification of Cryptic and Allosteric Pocket

141 compounds

This unique library of small heterocyclic electrophiles developed by the research group of Prof. György Keserű have been shown to be effective in finding tiny new binding pockets for different protein targets (MedChemComm 2019, Nat. Commun. 2020 and Pharmaceuticals 2022). The library combines the advantages of Astex’s MiniFrags in exploring unprecedented binding site with that of covalent binders in higher affinity and easier detection. It consists of six and five-membered heterocycles most abundant in drugs that are equipped with only one or two-atom covalent warheads. This makes it unique in contrast to those often used in covalent screening, much larger acrylamides and chloroacetamides which can significantly influence the binding mode of active molecules. Thus, applying the smallest possible covalent function helps to avoid promiscuity and keep the same recognition pattern of non-covalent scaffolds.

On the other hand, the electrophile-first approach proved to be an effective way of developing covalent drugs (Nat. Rev. Drug Discov. 2022). A number of covalent probes and drug candidates, including recent examples of Nirmatrelvir and Sotorasib have been developed using covalent screening techniques.

Covalent MiniFrags is a unique tool for searching of new binding pockets, elaboration of discovered hits and growing vector identification. The XChem facility at Diamond LightSource UK is a strategic partner in pioneering applications of Covalent MiniFrags.

Typical Formats

Catalog No.
Compounds
Amount
Format
Price

Catalog No.

CMF-141-5-Y-500

Compounds

141
1 plate

Amount

5 μL of 500 mM DMSO solutions

Plates and formats

384-well acoustic LDV plates, first two and last two columns empty

Price

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Catalog No.

CMF‑141‑25‑X‑100

Compounds

141
2 plates

Amount

25 μL of 100 mM DMSO solutions

Plates and formats

96-well plates, Greiner Cat. No 650201, round (U) bottom, 1 & 12 columns empty, 80 compounds per plate

Price

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Catalog No.

CMF‑141

Compounds

141

Amount

Custom

Plates and formats

Any custom format

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Сovalent MiniFrags

Library code: CMF‑141

Version: 20 September 2023

141 compounds

Key features

  • Most common nitrogen-containing heterocycles
  • The smallest covalent warheads
  • Experimentally characterized stability and intrinsic reactivity
  • Evaluated on a number of targets

 

Covalent MiniFrags Library consists of 85 heterocyclic electrophiles and 56 N-methylated functional heterocycles. Both subsets are described in detail in scientific publications and are now available for your research.

Bromodomain Library

Specially selected molecules to target bromodomains

15 360 compounds

Bromodomains are protein domains found in various proteins and are involved in the recognition of acetylated lysine residues on histone proteins. These domains are named after their ability to recognize the acetyl-lysine side chain, which has a similar shape to a bromide ion. Bromodomains are essential in regulating gene expression and chromatin structure, as acetylation of histones is associated with open chromatin and active gene transcription. Dysregulation of bromodomain-containing proteins has been implicated in several diseases, including cancer and inflammation. As a result, bromodomains have become a popular target for drug discovery efforts, with several small molecule inhibitors in development for cancer and other diseases.

We focused on the search of active compounds against the most important Bromodomain families: BET subfamily: includes BRD2, BRD3, BRD4, and BRDT bromodomains, which are characterized by an extended ZA loop that interacts with acetylated lysine residues on histones. GCN5-related subfamily: This subfamily includes the GCN5 and PCAF bromodomains found in histone acetyltransferases and have a shorter ZA loop than the BET subfamily. TAF1-like subfamily: TAF1 and TAF1L bromodomains are found in transcription factor TFIID and have an N-terminal extension that interacts with other complex subunits. ATAD2-like subfamily: ATAD2 and ATAD2B bromodomains are found in AAA+ ATPases and have a long ZA loop and a unique insertion between the second and third alpha-helices. Additionally, we run docking calculations for BPTF protein that also contains bromodomain.

Typical Formats

Catalog No.
Compounds
Amount
Format
Price

Catalog No.

BRD-15-0-Y-10

Compounds

15 360
48 plates

Amount

Assay-ready format < 300 nL

Plates and formats

384-well microplates, Corning #4514, 320 compounds per plate, first two and last two columns empty

Price

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Catalog No.

BRD-15-10-Y-10

Compounds

15 360
48 plates

Amount

10 µL of 10mM DMSO solutions

Plates and formats

384-well echo plates, Labcyte #LP-0200, 320 compounds per plate, first two and last two columns empty

Price

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Catalog No.

BRD-15-50-X-10

Compounds

15 360
192 plates

Amount

50 µL of 10mM DMSO solutions

Plates and formats

96-well plates, 80 compounds per plate, first and last columns empty; Greiner #781270

Price

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Catalog No.

BRD-15

Compounds

15 360

Amount

Custom

Plates and formats

Any custom format

Price

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Bromodomain target library

Library code: BRD-15

Version: 7 December 2023

15 360 compounds

sublibrary of EPG-38080

Library design

We used a structure-based approach, molecular docking calculations, as the main method for the library design. All available PDB structures for each of the bromodomain subfamilies were analyzed and extracted from PDB and PDBe. Unique "protein-ligand" complexes were selected for analysis. The following PDB structures were included in our study: BRD2 (4j1p, 4a9o, 5uew, 6ffe, 7l6d, 7l9j, and 7oe8), BRD3 (3s91 and 7l9l), BRD4 (7ajn, 7axr, and 7c2z), and BRDT (4flp, 7l9a, and 7mrg); PCAF (5fdz and 5fe5); TAF1 (5i1q, 6p38, and 7jjg); ATAD2 (6veo); and BPTF (5r4i, 6lu5, and 7lp0).

All simulations were performed with a common feature: the binding of a potential ligand to Asn inside the bromodomain binding pocket. All other binding points were dependent on the specific bromodomain and the structure of its native ligand. For example, in the left picture, the docking example of 7l6d is presented. The model is characterized by the following key features: (1) an h-bond acceptor to interact with Asn 429, an HOH molecule (which creates an h-bond bridge with Tyr 386), and an h-bond acceptor in the other part of the binding pocket to interact with the peptide backbone of Asp 377; (2) two aromatic groups to fill in the subpockets between Val 435, Leu 383, and between Pro 371, Leu 381; and (3) any atom group to fill in the subpocket among Tyr 428, Asn 429, and Leu 383. In contrast, in the right picture (5fe5), the model should contain slightly different binding properties: (1) an h-bond acceptor to interact with Asn 803, an HOH molecule (which creates an h-bond bridge with Tyr 760); (2) two aromatic groups to fill in the binding pocket and potentially create stacking interactions with Tyr 809.

Examples of molecular docking simulation to bromodomains

The molecular docking simulations to bromodomains were conducted using the following color scheme: red spheres represent h-bond acceptors, blue spheres represent h-bond donors, orange spheres represent aromatic groups, and grey spheres represent any other atom types. The protein and its native ligand are highlighted in grey, while an example of a docked ligand is shown in yellow.

Molecular properties

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