Repurposing Phytocompounds as JAK1 Inhibitors for Targeting Pancreatic Cancer: A Molecular Docking, ADMET, and MD Simulation Study

Abstract

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway plays a central role in the development and advancement of cancer. Janus kinase 1 (JAK1) is essential for the constitutive activation of STAT3, whose activation promotes the development of various cancers including pancreatic ductal adenocarcinoma. This research utilizes computational methods to discover possible phytochemical inhibitors of JAK1 as prospective anticancer treatments. We chose phytochemicals from the Naturally Occurring Plant-based Anti-cancer Compound Activity Target database and evaluated them against JAK1 through molecular docking simulation. Molecular docking showed that tylophorinidine and fisetin exhibited the most favorable docking-based binding strengths, showing scores of −9.9 and −9.1 kcal/mol, respectively. Thorough evaluations involving PASS, ADME/T, drug-likeness, pIC50, and cytotoxicity predictions were performed. Fisetin has surfaced as the leading candidate, demonstrating significant kinase inhibitor potential (Pa = 0.950), advantageous drug-like characteristics, and cytotoxic effects on pancreatic cancer cell lines. Molecular dynamics simulations verified the binding strength of fisetin, with root mean square deviation values consistently approximately 0.25–0.30 nm, similar to the benchmark drug erlotinib. Comprehensive interaction studies showed that fisetin establishes robust interactions with JAK1’s binding site, particularly a prominent hydrogen bond with Arg1007. These in silico findings suggest that fisetin could serve as a potential natural inhibitor of JAK1 in cancer therapy, highlighting the need for further validation through laboratory and animal-based experiments.

Received: 1 February 2025 | Revised: 13 May 2025 | Accepted: 23 July 2025

Conflicts of Interest

The authors declare that they have no conflicts of interest to this work.

Data Availability Statement

The data that support this work are available upon reasonable request to the corresponding author.

Author Contribution Statement

Kashif Abbas: Conceptualization, Writing – original draft. Mudassir Alam: Conceptualization, Resources, Writing – original draft, Project administration. Mohsin Hussain: Methodology, Data curation, Writing – original draft. Mohd Mustafa: Validation, Visualization. Safia Habib: Writing – review & editing, Supervision. Nazura Usmani: Investigation, Supervision.