Exploring the mechanism of action of spirooxindoles as a class of CDK2 inhibitors: a structure-based computational approach

Abstract

Cyclin-dependent kinase 2 (CDK2) regulates cell cycle checkpoints in the synthesis and mitosis phases and plays a pivotal role in cancerous cell proliferation. The activation of CDK2, influenced by various protein signaling pathways, initiates the phosphorylation process. Due to its crucial role in carcinogenesis, CDK2 is a druggable hotspot target to suppress cancer cell proliferation. In this context, several studies have identified spirooxindoles as an effective class of CDK2 inhibitors. In the present study, three spirooxindoles (SOI1, SOI2, and SOI3) were studied to understand their inhibitory mechanism against CDK2 through a structure-based approach. Molecular docking and molecular dynamics (MD) simulations were performed to explore their interactions with CDK2 at the molecular level. The calculated binding free energy for the spirooxindole-based CDK2 inhibitors aligned well with experimental results regarding CDK2 inhibition. Energy decomposition (ED) analysis identified key binding residues, including I10, G11, T14, R36, F82, K89, L134, P155, T158, Y159, and T160, in the CDK2 active site and T-loop phosphorylation. Molecular mechanics (MM) energy was identified as the primary contributor to stabilizing inhibitor binding in the CDK2 protein structure. Furthermore, the analysis of binding affinity revealed that the inhibitor SOI1 binds more strongly to CDK2 compared to the other inhibitors under investigation. It demonstrated a robust interaction with the crucial residue T160 in the T-loop phosphorylation site, responsible for kinase activation. These insights into the inhibitory mechanism are anticipated to contribute to the development of potential CDK2 inhibitors using the spirooxindole scaffold.

Publication DOI: https://doi.org/10.1039/D4CP00844H
Divisions: College of Engineering & Physical Sciences > School of Computer Science and Digital Technologies > Applied Mathematics & Data Science
Funding Information: The authors extend their appreciation to the Researchers Supporting Project number (RSPD2024R994), King Saud University, Riyadh, Saudi Arabia. The authors also acknowledge financial support for computational resources from Pakistan Science Foundation Proj
Additional Information: Copyright © The Royal Society of Chemistry, 2024. This is an accepted manuscript of an article published in Physical Chemistry Chemical Physics. The published version is available at: https://doi.org/10.1039/D4CP00844H
Publication ISSN: 1463-9084
Last Modified: 07 Oct 2024 17:25
Date Deposited: 11 Jun 2024 16:19
Full Text Link:
Related URLs: https://pubs.rs ... 4/cp/d4cp00844h (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2024-06-14
Published Online Date: 2024-05-13
Accepted Date: 2024-05-12
Authors: Abdjan, Muhammad Ikhlas
Shafiq, Muhammad
Nerukh, Dmitry (ORCID Profile 0000-0001-9005-9919)
Nur-e-Alam, Mohammad
Ul-Haq, Zaheer

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