Exploring Novel Furochochicine Derivatives as Promising JAK2 Inhibitors in HeLa cells: Integrating Docking, QSAR-ML, MD Simulations, and Experiments

Exploring Novel Furochochicine Derivatives as Promising JAK2 Inhibitors in HeLa cells: Integrating Docking, QSAR-ML, MD Simulations, and Experiments Научная публикация

Журнал

Computational and Structural Biotechnology Journal
ISSN: 2001-0370

Вых. Данные

Год: 2025, Том: 27, Страницы: 3625-3639 Страниц : 15 DOI: 10.1016/j.csbj.2025.08.007

Авторы

Todsaporn Duangjai ¹ , Sanachai Kamonpan ² , Aonbangkhen Chanat ³ , Geronikaki Athina ⁴ , Kartsev Victor ⁵ , Lichitsky Boris ⁶ , Komogortsev Andrey ⁶ , Maitarad Phornphimon ⁷ , Rungrotmongkol Thanyada ^1,8

Организации

1	Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
2	Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand.
3	Center of Excellence in Natural Products Chemistry (CENP), Department of Chemistry, Faculty of Science, Chulalongkorn University, Phayathai Road, Pathumwan, Bangkok 10330, Thailand.
4	Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
5	InterBioscreen, Moscow, Russia.
6	Zelinsky Institute of Organic Chemistry, Leninsky prospect, Moscow 119991, Russia.
7	Research Center of Nano Science and Technology, Department of Chemistry, College of Science, Shanghai University, Shanghai 200444, PR China.
8	Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok, Thailand.

Cervical cancer, largely driven by high-risk human papillomavirus (HPV), remains a global health challenge. Janus tyrosine kinase 2 (JAK2) has emerged as a promising therapeutic target for HPV-induced malignancies. This study employed both in silico and in vitro approaches to discover novel JAK2 inhibitors from a library of 76 furochochicine (FCC) derivatives. Twenty-nine compounds were selected via virtual screening, synthesized, and tested for cytotoxicity against HeLa cells. Four FCCs showed potent cytotoxicity with selectivity indices (SI) greater than 3. These cytotoxicity data were used to construct QSAR models with machine learning; eXtreme Gradient Boosting (XGB) yielded the best performance (RMSE = 0.177, R² = 0.831, MAPE = 2.93 %) and was used to predict additional FCC derivatives. FCC90 emerged as a lead compound with strong predictive accuracy (MAPE = 1.43 %) and selectivity (SI = 3.25). JAK2 kinase assays revealed strong inhibition by FCC6, FCC27, and FCC90 (IC₅₀ = 9.10–27.34 nM), with FCC6 and FCC27 surpassing ruxolitinib. Flow cytometry confirmed apoptosis and sub-G1 cell cycle arrest. Molecular dynamics simulations supported the stability of FCC–JAK2 complexes. Furthermore, all active compounds met extended Rule of Five (eRo5) criteria. These findings highlight the potential of FCC derivatives as JAK2 inhibitors for cervical cancer therapy.

Todsaporn D. , Sanachai K. , Aonbangkhen C. , Geronikaki A. , Kartsev V. , Lichitsky B. , Komogortsev A. , Maitarad P. , Rungrotmongkol T.
Exploring Novel Furochochicine Derivatives as Promising JAK2 Inhibitors in HeLa cells: Integrating Docking, QSAR-ML, MD Simulations, and Experiments
Computational and Structural Biotechnology Journal. 2025. V.27. P.3625-3639. DOI: 10.1016/j.csbj.2025.08.007 WOS Scopus OpenAlex

Web of science:	WOS:001553862400001
Scopus:	2-s2.0-105013505796
OpenAlex:	W4413118507

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