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). CDKs play a critical role in the G1- to S-phase checkpoint of the cell cycle (Fig. 1) [1-2]. Inhibition of cyclin-dependent kinases is a topic of major interest in current anticancer drug discovery research. Different classes of small-molecule inhibitors of these protein kinases have been identified during the past decade, and the structural basis of inhibition has been well elucidated by X-ray crystallography studies of members of the family . Several types of CDK inhibitors have so far been reported: flavopiridole, benzimidazopyrimidines, butyrolactone purine derivatives, staurosporine, indirubin, paullones, and others .
At Life Chemicals, we have designed a dedicated Screening Library of over 1,700 drug-like screening compounds targeting CDKs, using a unique approach [5-7]:
Our in-house method for receptor-based virtual screening of compounds is founded on a 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.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at firstname.lastname@example.org for any additional information and price quotations.
Cyclin-dependent Kinase 7 (CDK7) Screening Set
CDK7 kinase in complex with inhibitor ICEC0943 and ATP-gamma-S, deposited in the Protein Data Bank, has been used by Life Chemicals to design the CDK7 Focused and Targeted Set.
Docking-based virtual screening protocol (Glide by Schrödinger, SP mode) has been employed to search through the Life Chemicals HTS Compound Collection for potential cyclin-dependent kinase active site binders. No docking constraints have been used to allow the special position (SP) docking algorithm to explore as many ligand positions and orientations as possible.
Additionally, the 2D fingerprint similarity search was used. The Tanimoto similarity cut-off of 85 % was applied for screening a reference set of compounds known to be active against CDK7 kinase (data taken from the ChEMBL database). All compounds in the reference set were chosen in accordance with the accepted maximum activity value (IC50, Ki50 < 10 mM).1,300 drug-like screening compounds obtained by the virtual screening and subsequent similarity search filtering were selected for this CDK7 Kinase Screening Library.
Figure 2. Binding mode of the compound F2745-0227 in the CDK7 catalytic site. Molecular complex obtained by docking.
Cyclin-dependent Kinase 2 (CDK2) Targeted SetInitially, the Life Chemicals HTS Compound Collection was filtered according to the Lipinski and Veber Rules. Molecular docking was then performed, and its results were analyzed within the DOCK 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 small-molecule screening compounds were selected and included in the Life Chemicals CDK2 Kinase Screening Library.
Figure 3. Binding mode of the compound F0170-0601 in the CDK2 catalytic site. Molecular complex obtained by docking.
- Besson А, Dowdy SF, Roberts JM. CDK inhibitors: ceLI сус\е regulators and beyond. Dev Cell, 2008 14(2), 159-169.
- Malumbres M. Cyclin-dependent kinases. Genome Biol, 2014, 15, 122.
- Whittaker SR, Mallinger A, Workman P, Clarke PA. Inhibitors of cyclin-dependent kinases as cancer therapeutics. Pharmacol Ther. 2017;173:83-105.
- Łukasik P, Baranowska-Bosiacka I, Kulczycka K, Gutowska I. Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action. Int J Mol Sci. 2021;22(6):2806.
- Yuou Teng, Kui Lu, Qian Zhang, Lianbo Zhao, Yuna Huang, Angela Maria Ingarra, Hervé Galons, Tingshen Li, Shanshan Cui, Peng Yu, Nassima Oumata. Recent advances in the development of cyclin-dependent kinase 7 inhibitors. European Journal of Medicinal Chemistry, 2019, 183, 111641.
- Tang HC, Chen CY. Drug design of cyclin-dependent kinase 2 inhibitor for melanoma from traditional Chinese medicine. Biomed Res Int. 2014;798742.
- Ahmad B, Saeed A, Castrosanto MA, Amir Zia M, Farooq U, Abbas Z, Khan S. Identification of natural marine compounds as potential inhibitors of CDK2 using molecular docking and molecular dynamics simulation approach. J Biomol Struct Dyn. 2022 Oct 27:1-11. doi: 10.1080/07391102.2022.2135594. Epub ahead of print. PMID: 36300512.