Designed for efficient hit finding against a number of immune disorders, including RA
1 280 compounds
The library was designed to be a universal tool to search potential JAK-STAT pathway modulators. Protein structure-based analysis and scaffold-hopping approach were used to create an optimal in silico screening models. Additionally, ligand-based approach has been applied to enrich the library with topological analogs and similar compounds to reported actives.
Resulted library is as a generic starting point for ligand search, regardless of particular SH2 domain of interest, with high probability of initial hit discovery. The library was validated with in vitro screening against SRC SH2 domain resulting in 3.5 % of identified hits.
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Library design
All available structures of SH2 domain binding sites were analyzed and clustered based on their spatial molecular shape. After the alignment analysis and clustering structures with most different conformations were selected for virtual screening. Enamine MedChem filtered in-stock subset (~1 M compounds) with additional selection of compounds carrying peptidomimetic motifs was used for molecular docking calculations.
Multiple sequence alignment was applied to 120 SH2 domains contained within 110 proteins. Over 200 protein structures were extracted from Protein Data Bank (PDB): 66 NMR-based structures and 153 derived from X-ray crystallography experiments. As variation of the binding site conformation may significantly influence its binding properties, all files were split into individual structures, resulting in total structure count of 1633.
Key pharmacophore interaction points: pTyr binding pocket, carbonyl O in the binding site center, hydrophobic sub-pocket.
Solvent accessible molecular surface within 12 Å from the binding site center was used for calculation of shape-based numeric descriptors. 3D structures were clustered based on 3D shape similarity. 8 spatially diverse structures were selected for docking.
Table 1. Summary of protein 3D structures clustering results and structures selected for docking.
1
Centroid structure (PDB id, chain, NMR model)
1o49, chain A
Centroid structure: organism, gene, domain
Homo Sapiens SRC SH2
Structures in cluster
223
2
Centroid structure (PDB id, chain, NMR model)
2fci, chain A, model 6
Centroid structure: organism, gene, domain
Bos Taurus PLCG1 SH2-2
Structures in cluster
48
3
Centroid structure (PDB id, chain, NMR model)
2ge9, chain A, model 15
Centroid structure: organism, gene, domain
Homo Sapiens BTK SH2
Structures in cluster
72
4
Centroid structure (PDB id, chain, NMR model)
3in7, chain A
Centroid structure: organism, gene, domain
Homo Sapiens GRB2 SH2
Structures in cluster
183
5
Centroid structure (PDB id, chain, NMR model)
2jyq, chain A, model 9
Centroid structure: organism, gene, domain
Homo Sapiens GRB2 SH2
Structures in cluster
114
6
Centroid structure (PDB id, chain, NMR model)
2k7a, chain B, model 5
Centroid structure: organism, gene, domain
Mus Musculus ITK SH2
Structures in cluster
218
7
Centroid structure (PDB id, chain, NMR model)
2kk6, chain A, model 14
Centroid structure: organism, gene, domain
Homo Sapiens FER SH2
Structures in cluster
149
8
Centroid structure (PDB id, chain, NMR model)
1uus, chain A
Centroid structure: organism, gene, domain
Dictyostelium Discoideum DSTA SH2
Structures in cluster
129
Virtual screening against Stat3beta:
- Collaborator: Gyeong Baeg, NYMC
Chemical compounds are significantly smaller in size than the natural peptide interacting with this target. Therefore, when creating the library, we tried to fill all potential sub-pockets available near the phosphotyrosine binding site. The entire available surface of the protein was conditionally broken down into 5 models and proceeding from this was carried out post-docking analysis. As an example, the first two models:
STAT3 models: Schematic representation of ligand binding pocket
The largest diversity library with high MedChem tractability
460 160 compounds
Hit Locator Library (HLL) represents the entire Enamine’s Screening Collection of 4.6M+ compounds. Smart clustering approach and elaborated MedChem filters together with thoughtful molecular parameters restriction allowed us to design an ultimate HTS Library.
Typical Formats
Hit Locator Library is available for supply in various pre-plated formats, including the following most popular ones:
Catalog No.
HLL‑460-0-Z-10
Compounds
460 160
360 plates
Amount
≤ 300 nL of 10 mM of DMSO solutions
Plates and formats
1536-well Echo LDV microplates, first and last four columns empty, 1280 compounds per plate
Price
Catalog No.
HLL‑200-10-Y-10
Compounds
200 000
625 plates
Amount
10 µL of 10 mM DMSO solutions
Plates and formats
384-well, Echo Qualified LDV microplates #001-12782 (LP-0200), first and last two columns empty, 320 compounds per plate
Price
Catalog No.
HLL‑300-50-Y-10
Compounds
300 160
938 plates
Amount
50 μL of 10 mM DMSO solutions
Plates and formats
384-well, Greiner Bio-One plates #781280, first and last two columns empty, 320 compounds per plate
Price
Catalog No.
Library & follow-up package
Plates and formats
HLL‑460-0-Z-10 screening library 460 160 cmpds, hit resupply, analogs from 4.6M+ stock and synthesis from REAL Space
Price
*We will be happy to provide our library in any other most convenient for your project format. Please select among the following our standard microplates: Greiner Bio-One 781270, 784201, 781280, 651201 or Echo Qualified 001-12782 (LP-0200), 001-14555 (PP-0200), 001-6969 (LP-0400), C52621 or send your preferred labware. Compounds pooling can be provided upon request.
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5 120 compounds
Library design
Carefully considered approach to the design our largest screening library aims to deliver the most reliable source of initial hits. Each compound in the library passed stringent MedChem filters and QC control. Construction of this HTS Library allow to get initial SAR data immediately after a first screen and will help you to determine safe hits, which you can follow more secure than any other from commercial diversity libraries. The main focus at medicinal chemistry hand was fixed on the lead-like molecules to give more space for evolution of identified hits. At the same time, we were trying to focus on robust chemistry, which should not bring troubles with synthesis of scaffolds or their derivatisation. Our deep knowledge in synthetic chemistry already over 25 years’ experience allowed us to rate molecules by synthetic feasibility, which has been used as additional evaluation in the design of the largest Enamine Screening Library.
Key features
- No singletons, at least 3 compounds per cluster
- Immediate initial SAR, scaffold-secured
- Represents entire Enamine Screening Collection
- Lead-like compounds
- Hit confirmation & follow-up support
Along with all industry affiliated MedChem filters, sieve visual control of the core scaffolds (over 47k) have been applied. We believe that our effort will bring you a valuable hits. Some examples are represented below
Example of a cluster series
Cluster 458692
Cluster 103875
Representation of Hit Locator Library coverage of the entire Enamine stock Screening Collection
Molecular properties
Top-quality diverse library of recently synthesized compounds
50 240 compounds
The success of high throughput screening in finding decent starting points for drug discovery heavily depends on the quality of the compound library. Compound screening libraries nowadays must bear an essential degree of novelty, possess contemporary lead-like properties and be built on “live chemistry” that can supply related chemical entities.
Enamine is constantly updating its Screening catalog with at least 225 000 newly synthesized compounds each year. These molecules are built on novel chemistry with use of the latest achievements in parallel chemistry and following industry trends in molecular properties and structural features. Every new library to be synthesized went through serial filters and is focused to bring novelty in a certain drug discovery area.
Discovery Diversity Sets (DDS) are aimed to bring latest chemistry to our customers within a smart clustering approach. Discovery Diversity Sets are based only on the lead-like compounds including representatives of all three main screening collections – HTS, Advanced, and Premium.
Typical Formats
Discovery Diversity Set is available for supply in various pre-plated formats, including the following most popular ones:
Catalog No.
DDS-50-0-Z-10
Compounds
50 240
40 plates
Amount
≤ 300 nL of 10 mM of DMSO solutions
Plates and formats
1536-well Echo LDV microplates, first and last four columns empty, 1280 compounds per plate
Price
Catalog No.
DDS-50-10-Y-10
Compounds
50 240
157 plates
Amount
≤ 10 µL of 10 mM DMSO solutions
Plates and formats
384-well, Echo Qualified LDV microplates #001-12782 (LP-0200), first and last two columns empty, 320 compounds per plate
Price
Catalog No.
DDS-50-50-Y-10
Compounds
50 240
157 plates
Amount
50 μL of 10 mM DMSO solutions
Plates and formats
384-well, Greiner Bio-One plates #781280, 1,2 and 23,24 columns empty, 320 compounds per plate
Price
Catalog No.
Library & follow-up package
Plates and formats
DDS-50-10-Y-10 screening library 50 240 cmpds, hit resupply, analogs from 4.3M stock and synthesis from REAL Space
Price
*We will be happy to provide our library in any other most convenient for your project format. Please select among the following our standard microplates: Greiner Bio-One 781270, 784201, 781280, 651201 or Echo Qualified 001-12782 (LP-0200), 001-14555 (PP-0200), 001-6969 (LP-0400), C52621 or send your preferred labware. Compounds pooling can be provided upon request.
The hits from Discovery Diversity Sets are expected to be fast and easy to produce follow-up SAR libraries.
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Key features
- Novel compounds
- No singletons, 3-5 compounds per cluster
- 10 234 clusters in DDS-50
- No PAINS, only MedChem friendly compounds
- Express follow-up guaranteed
Distribution of clusters size (# of compounds with a cluster) in the library
Examples of molecules within a cluster
PPI-like scaffolds Cluster 4
GPCR-like structures Cluster 14
CNS-like scaffold Cluster 34
Kinase scaffold Cluster 11062
Molecular properties
High-quality diverse library of latest compounds
10 240 compounds
The success of high throughput screening in finding decent starting points for drug discovery heavily depends on the quality of the compound library. Compound screening libraries nowadays must bear an essential degree of novelty, possess contemporary lead-like properties and be built on “live” chemistry that can supply related chemical entities.
Only within last three years Enamine synthesized over 790 000 screening compounds for its public catalog. These substances feature a new structural diversity of Enamine unique building blocks and scaffolds. Having the largest commercial screening collection in the world, Enamine remains the only library producer that keeps enhancing its collection with significant number of new compounds each year. The renowned quality of compounds has been distilled in the design of two Discovery Diversity Sets (DDS). Discovery Diversity Sets are based only on the lead-like compounds including representatives of all three screening collections of Enamine – HTS, Advanced, and Premium.
The Discovery Diversity Sets are highly recommended for random screening against new as well as popular targets because of diversity of scaffolds and presence of latest building blocks.
Discovery Diversity Sets have been plated at 10 mM concentration in DMSO and can be swiftly supplied in different customized formats including following most popular options:
Typical Formats
Discovery Diversity Set is available for supply in various pre-plated formats, including the following most popular ones:
Catalog No.
DDS-10-0-Z-10
Compounds
10 240
8 plates
Amount
≤ 300 nL of 10 mM of DMSO solutions
Plates and formats
1536-well Echo LDV microplates, first and last four columns empty, 1280 compounds per plate
Price
Catalog No.
DDS-10-10-Y-10
Compounds
10 240
32 plates
Amount
≤ 10 µL of 10 mM DMSO solutions
Plates and formats
384-well, Echo Qualified LDV microplates #001-12782 (LP-0200), first and last two columns empty, 320 compounds per plate
Price
Catalog No.
DDS-10-50-Y-10
Compounds
10 240
32 plates
Amount
50 μL of 10 mM DMSO solutions
Plates and formats
384-well, Greiner Bio-One plates #781280, 1,2 and 23,24 columns empty, 320 compounds per plate
Price
Catalog No.
Library & follow-up package
Plates and formats
DDS-10-10-Y-10 screening library 10 240 cmpds, hit resupply, analogs from 4.6M+ stock and synthesis from REAL Space
Price
*We will be happy to provide our library in any other most convenient for your project format. Please select among the following our standard microplates: Greiner Bio-One 781270, 784201, 781280, 651201 or Echo Qualified 001-12782 (LP-0200), 001-14555 (PP-0200), 001-6969 (LP-0400), C52621 or send your preferred labware. Compounds pooling can be provided upon request.
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The hits discovered from Discovery Diversity Sets are expected to easily yield lead compounds. All identified hits can be readily followed with analogues either from stock or from new syntheses through our REAL database technology. All building blocks for lead optimization programs are readily available from Enamine stock.
Key features
- Novel compounds
- No PAINS, only medchem friendly compounds
- Express follow-up guaranteed
Comparative analysis of DDSs and commercially available compounds
74% of the compounds from DDS 10K are available exclusively at Enamine
Examples of the molecules
Molecular properties
Enamine’s Screening Collection of 4.6M+ compounds and over 200k Building Blocks is an unprecedented source for Hit Finding projects. Continuous collection enhancement with new chemotypes derived through development of new synthetic approaches provides versatile opportunity for small molecules Drug Discovery.
We offer a number of high-quality Diversity Libraries different in size and design intention.
Product catalog
HLL-460
Size
460 160
compounds
Description
The largest diversity library with high MedChem tractability
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HLL-200
Size
200 000
compounds
Description
Sublibrary of HLL-460
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HLL-100
Size
100 160
compounds
Description
Sublibrary of HLL-460
Download file
DDS-50
Size
50 240
compounds
Description
Top-quality diverse library of recently synthesized compounds
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DDS-10
Size
10 240
compounds
Description
High-quality diverse library of latest compounds
Download file
CSL-11760
Size
11 760
compounds
Description
Diverse covalent library with most demanded warhead types
Download file
PSL-5760
Size
5 760
compounds
Description
Special diversity library created for Phenotypic Screens
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PAINS-320
Size
320
compounds
Description
Special diverse selection of frequent hitters
Download file
Size
83
compounds
Description
Curated selection of frequent hitters
MCR-500
Size
500
compounds
Descriptions
Original design beyond Ro5 compounds
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Support
We offer comprehensive support in developing your hit compounds. Naturally such programs are realised most efficiently when biological actives originate from our screening collection. However, even if the hit compounds are from the collections of other vendors lead identification and optimization projects can proceed most productively in our hands. Sometimes for this we only need to synthesize first examples of the given chemical series and validate synthesis route.
