Computational Evaluation of Potent Alkaloids as Promising CDK2 Inhibitors
DOI:
https://doi.org/10.53555/jaz.v43i1.5320Keywords:
CDK2 inhibitors, alkaloids, molecular docking, ADMET analysis, drug-likeness, anticancer agents, computational modeling.Abstract
Cyclin-dependent kinase 2 (CDK2) plays a crucial regulatory role in cell-cycle progression, making it an attractive target for anticancer drug development. In this study, six bioactive alkaloids—berberine, evodiamine, matrine, piperine, sanguinarine, and tetrandrine—were computationally evaluated to identify potent CDK2 inhibitors. The selected molecules, chosen for their well-documented anticancer activities, were subjected to a systematic workflow comprising molecular docking, ADMET prediction, drug-likeness assessment, and environmental toxicity analysis. Molecular docking performed using PyRx and AutoDock Vina revealed that several alkaloids exhibit strong binding affinity toward CDK2, with sanguinarine (–10.3 kcal/mol), evodiamine (–9.8 kcal/mol), and berberine (–9.3 kcal/mol) outperforming the native ligand. Their superior interactions were attributed to favorable hydrogen bonding, electrostatic forces, and extensive hydrophobic contacts within the CDK2 active site. ADMET analysis conducted through SwissADME and ADMETlab 3.0 demonstrated that evodiamine, piperine, and matrine possess balanced pharmacokinetic properties, while berberine and sanguinarine showed moderate oral absorption and acceptable safety profiles. Drug-likeness evaluation indicated full compliance with Lipinski’s rules for all compounds, with evodiamine and matrine exhibiting the highest QED values. Toxicity modeling highlighted moderate risks for certain molecules; however, the potent compounds remained within manageable safety margins. Environmental toxicity assessment further differentiated the compounds based on bioaccumulation and aquatic toxicity potential. Overall, the integrated computational approach identified sanguinarine, evodiamine, and berberine as the most promising CDK2 inhibitors. Their strong binding affinities, supportive ADMET characteristics, and favorable drug-likeness profiles warrant further experimental validation to advance them as potential anticancer therapeutic candidates.
Downloads
References
1. Knudsen ES, Witkiewicz AK, Sanidas I, Rubin SM. Targeting CDK2 for cancer therapy. Vol. 44, Cell Reports. 2025.
2. Zeng Y, Ren X, Jin P, Fan Z, Liu M, Zhang Y, et al. Inhibitors and PROTACs of CDK2: challenges and opportunities. Vol. 19, Expert Opinion on Drug Discovery. 2024. p. 1125–48.
3. Arora M, Moser J, Hoffman TE, Watts LP, Min M, Musteanu M, et al. Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity. Cell. 2023;186(12):2628-2643.e21.
4. Bai Y, Aodeng G, Ga L, Hai W, Ai J. Research Progress of Metal Anticancer Drugs. Vol. 15, Pharmaceutics. 2023.
5. Kumar G, Virmani T, Sharma A, Pathak K. Codelivery of Phytochemicals with Conventional Anticancer Drugs in Form of Nanocarriers. Vol. 15, Pharmaceutics. 2023.
6. Huang Y, Cao S, Zhang Q, Zhang H, Fan Y, Qiu F, et al. Biological and pharmacological effects of hexahydrocurcumin, a metabolite of curcumin. Vol. 646, Archives of Biochemistry and Biophysics. 2018. p. 31–7.
7. Zhang L, Yan M, Liu C. A comprehensive review of secondary metabolites from the genus Agrocybe: Biological activities and pharmacological implications. Vol. 15, Mycology. 2024. p. 162–79.
8. Onukwuli CO, zuchukwu CEI, Ugwu OPC. Exploring Phytochemicals for Diabetes Management: Mechanisms, Efficacy, and Future Directions. Newport Int J Res Med Sci. 2024;5(2):7–17.
9. Koche D, Shirsat R, Kawale M. An Overerview of Major Classes of Phytochemicals: Their Types and Role in Disease Prevention. Hislopia J. 2016;9(1/2):1–11.
10. Rozirwan, Nanda, Nugroho RY, Diansyah G, Muhtadi, Fauziyah, et al. Phytochemical composition, total phenolic content and antioxidant activity of Anadara granosa (Linnaeus, 1758) collected from the east coast of South Sumatra, Indonesia. Baghdad Sci J. 2023;20(4):1258–65.
11. He A, Wu M, Pu Y, Li R, Zhang Y, He J, et al. Fluoxetine as a Potential Therapeutic Agent for Inhibiting Melanoma Brain and Lung Metastasis: Induction of Apoptosis, G0/G1 Cell Cycle Arrest, and Disruption of Autophagy Flux. J Cancer. 2024;15(12):3825–40.
12. Smith JJ, Xiao Y, Parsan N, Medwig-Kinney TN, Martinez MAQ, Moore FEQ, et al. The SWI/SNF chromatin remodeling assemblies BAF and PBAF differentially regulate cell cycle exit and cellular invasion in vivo. PLoS Genet. 2021;18(1).
13. Swanson K, Walther P, Leitz J, Mukherjee S, Wu JC, Shivnaraine R V., et al. ADMET-AI: a machine learning ADMET platform for evaluation of large-scale chemical libraries. Bioinformatics. 2024;40(7).
14. Venkataraman M, Rao GC, Madavareddi JK, Maddi SR. Leveraging machine learning models in evaluating ADMET properties for drug discovery and development. ADMET DMPK. 2025;13(3).
15. Zuo Y, Zhang C zheng, Ren Q, Chen Y, Li X, Yang J rui, et al. Activation of mitochondrial-associated apoptosis signaling pathway and inhibition of PI3K/Akt/mTOR signaling pathway by voacamine suppress breast cancer progression. Phytomedicine. 2022;99.
16. Saini N, Goswami V, Thakor E, Vasava M, Patel B. Anticancer Potential of Piperidine Containing Small Molecule Targeted Therapeutics. Vol. 9, ChemistrySelect. 2024.
17. Duda-Madej A, Viscardi S, Szewczyk W, Topola E. Natural Alkaloids in Cancer Therapy: Berberine, Sanguinarine and Chelerythrine against Colorectal and Gastric Cancer. Int J Mol Sci. 2024;25(15).
18. Shaheen A, Fida H, Akhmedov S, Rasulbek E, Ataullaev Z. In Silico Study of Alkaloids as Potential Cyclin-Dependent Kinase (CDK) Inhibitors. 2025;1(4):324–35. Available from: https://jpscc.samipubco.com/article_235766_f9de3c3b67552b56d5e748fb40a24329.pdf
19. Khan S, Kale M, Siddiqui F, Nema N. Novel pyrimidine-benzimidazole hybrids with antibacterial and antifungal properties and potential inhibition of SARS-CoV-2 main protease and spike glycoprotein. Digit Chinese Med. 2021;4(2):102–19.
20. Shastri MA, Gadhave R, Talath S, Wali AF, Hani U, Puri S, et al. In silico Screening, Synthesis, and in vitro Enzyme Assay of Some 1,2,3-Oxadiazole-linke Tetrahydropyrimidine-5-carboxylate Derivatives as DPP-IV Inhibitors for Treatment of T2DM. Chem Methodol. 2024;8(11):800–19.
21. Suryawanshi RM, Shimpi RB, Muralidharan V, Nemade LS, Gurugubelli S, Baig S, et al. ADME, Toxicity, Molecular Docking, Molecular Dynamics, Glucokinase activation, DPP-IV, α-amylase, and α-glucosidase Inhibition Assays of Mangiferin and Friedelin for Antidiabetic Potential. Chem Biodivers [Internet]. 2025 Dec 23; Available from: https://onlinelibrary.wiley.com/doi/10.1002/cbdv.202402738
22. Suryawanshi RM, Shimpi RB, Muralidharan V, Nemade LS, Gurugubelli S, Baig S, et al. ADME, Toxicity, Molecular Docking, Molecular Dynamics, Glucokinase activation, DPP-IV, α-amylase, and α-glucosidase Inhibition Assays of Mangiferin and Friedelin for Antidiabetic Potential. Chem Biodivers. 2025;22(5).
Downloads
Published
Issue
Section
License
Copyright (c) 2022 A.A. Kazi
This work is licensed under a Creative Commons Attribution 4.0 International License.
