Integrated <i>in silico</i> approaches reveal xanthone scaffold compounds as promising CDK2 inhibitors

Le Thi Thuy Huong; Bui Nguyen Thanh Long; Tran Van Lang; Pham Minh Quan

doi:10.15625/2525-2518/24123

Author affiliations

Authors

Le Thi Thuy Huong \(^1\) Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Street, Nghia Do Ward, Ha Noi, Viet Nam
\(^2\) Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Street, Nghia Do Ward, Ha Noi, Viet Nam
Bui Nguyen Thanh Long \(^1\) Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Street, Nghia Do Ward, Ha Noi, Viet Nam
Tran Van Lang \(^3\) Ho Chi Minh City University of Foreign Languages - Information Technology, 828 Su Van Hanh, Hoa Hung Ward, Ho Chi Minh City, Viet Nam https://orcid.org/0000-0002-8925-5549
Pham Minh Quan \(^1\) Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Street, Nghia Do Ward, Ha Noi, Viet Nam
\(^2\) Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Street, Nghia Do Ward, Ha Noi, Viet Nam https://orcid.org/0000-0001-6922-1627

DOI:

https://doi.org/10.15625/2525-2518/24123

Keywords:

xanthone, anticancer, molecular docking, molecular dynamic, ADMET, CDK2

Abstract

Cyclin-dependent kinase 2 is a pivotal regulator of the eukaryotic cell cycle, and its hyperactivation is a hallmark of various human malignancies. Consequently, identifying potent CDK2 inhibitors remains a primary objective in anticancer drug discovery. In this study, we employed an integrated in silico approach to evaluate a library of 3000 xanthone derivatives as potential CDK2 inhibitors. Initial high-throughput molecular docking identified compounds 313 and 481 as the potential inhibitors. Subsequent 20 ns molecular dynamics simulations confirmed the structural stability of the complexes, with all-atom RMSD values equilibrating at approximately 0.2 nm. Interaction analysis revealed that these inhibitors establish robust hydrogen bonds with essential residues, including Leu83 and Asp145, supported by an extensive hydrophobic network. While ADMET profiling indicated low acute toxicity and no tumorigenic potential, challenges regarding oral bioavailability and predicted mutagenicity were observed. These findings highlight compounds 313 and 481 as promising natural lead scaffolds that merit further structural optimization for the development of novel targeted cancer therapies.

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