Fusion of Structure and Ligand Based Methods for Identification of Novel CDK2 Inhibitors
Priya Mahajan1, Gousia Chashoo1, Monika Gupta1
1Discovery Informatics, ‡Cancer Pharmacology, §Medicinal Chemistry, and ∥Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180001, India.
Abstract:
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.
Insights
Researchers identified new compounds that inhibit CDK2, a key protein in cell division and cancer growth. This discovery offers potential new treatments for cancer by targeting abnormal cell proliferation.
Area of Science:
- Biochemistry and Molecular Biology
- Pharmacology and Drug Discovery
- Computational Chemistry
Background:
- Cyclin-dependent kinases (CDKs) are crucial for cell cycle regulation.
- Overexpression of CDK2 is linked to cancer cell hyperproliferation, making it a therapeutic target.
- Targeting CDK2 activity is a promising strategy for anticancer drug development.
Purpose of the Study:
- To identify novel chemical entities with potent CDK2 inhibitory activity.
- To utilize computational drug design approaches for screening large compound libraries.
- To discover new lead compounds for anticancer medication development.
Main Methods:
- Screening of a 50,000-compound library using ligand and structure-based computational drug design.
- In vitro evaluation of identified compounds for CDK2 inhibition.
- Molecular dynamics (MD) studies to analyze inhibitor binding and stability.
Main Results:
- 110 compounds were initially identified through computational screening.
- Seven compounds demonstrated over 50% inhibition of CDK2 at 10 μM in vitro.
- MD studies confirmed the stability of inhibitors and identified key binding residues (Glu81, Leu83).
Conclusions:
- Four novel chemical entities with significant CDK2 inhibitory activity were identified.
- The study validates computational approaches for discovering targeted cancer therapeutics.
- These findings provide a foundation for developing new CDK2-targeted anticancer drugs.
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