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

Muhammad Ikhlas Abdjan, Muhammad Shafiq, Dmitry Nerukh, Mohammad Nur-e-Alam, Zaheer Ul-Haq

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)16139-16152
Number of pages14
JournalPhysical Chemistry Chemical Physics
Issue number22
Early online date13 May 2024
Publication statusPublished - 14 Jun 2024

Bibliographical note

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


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