Fusion of Structure and Ligand Based Methods for Identification of Novel CDK2 Inhibitors

• Published in: Journal of chemical information and modeling 2017-08, Vol.57 (8), p.1957-1969
• Main Authors: Mahajan, Priya, Chashoo, Gousia, Gupta, Monika, Kumar, Amit, Singh, Parvinder Pal, Nargotra, Amit
• Format: Article
• Language: English
• Subjects: Cancer; Cell cycle; Cell division; Cells; Crystal structure; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-Dependent Kinase 2 - chemistry; Cyclin-Dependent Kinase 2 - metabolism; Drug Evaluation, Preclinical - methods; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Identification methods; Inhibitors; Inhibitory Concentration 50; Kinases; Lead compounds; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Pharmacology; Protein Conformation
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.7b00293

Cyclin dependent kinases play a central role in cell cycle regulation which makes them a promising target with multifarious therapeutic potential. CDK2 regulates various events of the eukaryotic cell division cycle, and the pharmacological evidence indicates that overexpression of CDK2 causes abnormal cell-cycle regulation, which is directly associated with hyperproliferation of cancer cells. Therefore, CDK2 is regarded as a potential target molecule for anticancer medication. Thus, to decline CDK2 activity by potential lead compounds has proved to be an effective treatment for cancer. The availability of a large number of X-ray crystal structures and known inhibitors of CDK2 provides a gateway to perform efficient computational studies on this target. With the aim to identify new chemical entities from commercial libraries, with increased inhibitory potency for CDK2, ligand and structure based computational drug designing approaches were applied. A druglike library of 50,000 compounds from ChemDiv and ChemBridge databases was screened against CDK2, and 110 compounds were identified using the parallel application of these models. On in vitro evaluation of 40 compounds, seven compounds were found to have more than 50% inhibition at 10 μM. MD studies of the hits revealed the stability of these inhibitors and pivotal role of Glu81 and Leu83 for binding with CDK2. The overall study resulted in the identification of four new chemical entities possessing CDK2 inhibitory activity.