Cyclin-dependent Kinases 2 (CDK2) Focused Library

The cell division cycle is controlled by cyclin-dependent kinases (CDKs) which consist of a catalytic subunit (cdk1-cdk8) and a regulatory subunit (cyclin A – cyclin H). The cyclin-dependent kinase 2 (CDK2) plays a critical role in the G1- to S-phase checkpoint of the cell cycle. Inhibition of cyclin-dependent kinases is a topic of major interest in current anticancer agents research. Different classes of chemical inhibitors of these enzymes have been identified during the past decade and the structural basis of inhibition has been well elucidated by X-ray crystallography studies of one member of the family, CDK2. Several types of CDKs inhibitors have so far been described: staurosporine, flavopiridole, butyrolactone purine derivatives, indirubin, paullones, benzimidazopyrimidines and others [1].

Life Chemicals has generated its Cyclin-dependent Kinases 2 (CDK2) Focused Library, usinga unique approach. Our proprietary method for receptor-based virtual screening of compounds includes powerful combination of drug-likeness filtering, molecular docking, re-scoring, key intermolecular hydrogen bonds and hydrophobic interaction detection and, finally, visual inspection of ligand-receptor complexes.

First, the stock collection was filtered according to the Lipinski and Veber Rules:

ClogP

-2 - 5

MW

150 - 500

number of H-donors

0 - 5

number of H-acceptors

0 - 9

number of rotatable bonds

0 - 10

TPSA

140 Å2

number of NO2 groups

≤ 2

number of S atoms

≤ 1

number of halogen atoms

≤ 5, no iodine containing compounds

Molecular docking was performed and its results were analyzed within DOCK 4.0-6.0 program. Molecular dynamics (MD) simulations and preparation of protein structures were carried out by GROMACS software. Ligand molecules were processed with GAMESS and GROMACS.

As a result, over 400 compounds were selected and included into the Life Chemicals CDK2 Focused Library.

References

1. Besson A, Dowdy SF, Roberts JM. CDK inhibitors: cell cycle regulators and beyond. Dev Cell, 2008 14(2), 159-169.