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Kynurenine Pathway Library

12 300 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.

Target selection

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).

Target Selection

Screening models preparation & validation

All available 3D structures of the targets were retrieved from PDB. Alternate superposition and comparison of the 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.

Binding site of IDO1 (2D0T) Binding site of IDO1 (two main subpockets)
Binding site of IDO1 (4PK5)

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.

Binding site of IDO1 (2D0T) Binding site of IDO1 (4PK5)

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

in silico screening IC50 = 180 nm in silico screening
in silico screening IC50 = 43 nm in silico screening
in silico screening IC50 = 4200 nm in silico screening

Ligand-base Pharmacophore models used for in silico screening.

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

Pocket class IDO TDO 3-HAO KATs KMO
Total number of compounds
(result of ligand search)
5 360 6 600 1 000 850 2 840

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



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