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Designed for discovery of new regulators of methabolic disorders

13 120 compounds

The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD+) from the degradation of tryptophan. Disruption in the pathway is associated with wide range of diseases and disorders including infectious diseases (e.g. HIV), neurological disorders (Alzheimer’s disease (AD), Huntington’s disease (HD) and ALS), affective disorders (schizophrenia, depression and anxiety), autoimmune diseases, peripheral conditions and malignancy. The aim of our work was to conduct searches for new potential active compounds for the kynurenine pathway, which, in turn, could be used as convenient and quality starting points for early drug development.

Typical Formats

Kynurenine Pathway Library is available for supply in various pre-plated formats, including the following most popular ones:

Catalog No.
Compounds
Amount
Format*
Price

Catalog No.

KYN-13-0-Z-10

Compounds

13 120
11 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

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Catalog No.

KYN-13-10-Y-10

Compounds

13 120
41 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

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Catalog No.

KYN-13-50-Y-10

Compounds

13 120
41 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

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*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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Kynurenine Pathway Library

Library code: KYN-13

Version: 17 May 2023

13 120 compounds

IDO Targeted Library

Library code: IDO-4800

Version: 13 August 2024

4 800 compounds at 10 mM in DMSO

TDO Focused Library

Library code: TDO-5120

Version: 13 August 2024

5 120 compounds

KMO Focused Library

Library code: KMO-3200

Version: 13 August 2024

3 200 compounds

Library design

The search of potential actives was performed using all available protein and ligand structural data for the following targets: indoleamine dioxygenase (IDO), tryptophan dioxygenase (TDO), 3-hydroxyanthranilic acid dioxygenase (3-HAO), kynurenine aminotransferases (KATs), kynurenine 3-monooxygenase (KMO).

Fig. 1. The kynurenine pathway of tryptophan degradation in mammals.

Screening Models preparation and validation

All available 3D structures of the targets were retrieved from PDB. Alternate superposition and comparison of the protein structures showed high sequence identity in every separate protein target > 90 % with RMSD in a range 0.4 - 0.71 Å2. Considering all representative structures only one has been selected for model preparation taking into account ligand binding parameters (protein- native ligand) and geometric parameters of the binding sites.

Fig. 2.Binding site of IDO1 (2D0T (top), 4PK5 (bottom) and example two main subpockets (in blue and yellow) used for molecular docking).

Molecular docking & Pharmacophore search

Basing on compounds with known activity and “protein–native ligand” complexes, ligand-based (IDO: 3, TDO: 4, KATs: 3, KMO: 2) and structure-based (IDO: 3, TDO: 6, 3-HAO: 2, KATs: 3, KMO: 4) pharmacophore models were build and validated. Drug-like Enamine database of over 1M compounds were then screened.

Fig. 3. Results of molecular docking: superposition of native (grey) and hit ligands (yellow) with representation of structure-based pharmacophore features.

Examples of the molecules

Fig. 4. Ligand-based Pharmacophore models used for in silico screening.

Number of compounds in targeted libraries after molecular docking calculation and pharmacophore searches:

Target Name

IDO

TDO

3-HAO

KATs

KMO

Number of compounds in the library

4 800

5 120

1 000

1 000

3 200

Careful analyzes of proteins and their ligand interactions involved in kynurenine pathway were performed. The iterative in silico searches using all available state-of-the-art methodologies were curried-out to yield unique sets of potentially active molecules. Chemotype control was used to enrich the libraries with structural motifs of true positives and new “patent-free” structural cores.

Developed targeted sets are intended for high-probability initial hit discovery in one step for any particular target.

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