Kynurenine Pathway Library

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

Catalog No.
Compounds
Amount
Format
Price

Catalog No.

KYN-13-0-Y-10

Compounds

13 120
41 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.

KYN-13-10-Y-10

Compounds

13 120
41 plates

Amount

10 µL of 10mM DMSO stock 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.

KYN-13-50-X-10

Compounds

13 120
164 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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Kynurenine Pathway Library

Library code: KYN-13

Version: 17 May 2023

13 120 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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