ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Discovery of potential JAK2 inhibitor: In silico molecular docking and molecular dynamics study for colon cancer therapy

Bavya Chandrasekhar, Honglae Sohn, and Thirumurthy Madhavan

Computational Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, SRM Institute of Science and Technology, Potheri, Chengalpattu District, Kattankulathur, India

E-mail: thiru.murthyunom@gmail.com

Received: 22 February 2025  Accepted: 6 May 2025

Abstract:

Colorectal cancer is the third leading cause of cancer worldwide, following lung and breast cancer. With an alarming prevalence, the disease is associated with abnormalities in the JAK2/STAT3 signalling pathway, which contributes to processes such as apoptosis and cell proliferation. This underscores a need for novel therapeutic strategies targeting this pathway to address treatment resistance and enhance efficacy. This study aimed to identify an effective synthetic drug for colon cancer by targeting the JAK2 protein. We employed computational methodologies, including molecular docking, cross-docking, and molecular dynamics (MD) simulations, particularly utilizing the Discovery Diversity Set from the Enamine library. Ten compounds with significantly greater binding affinities to JAK2 than the reference inhibitor fedratinib were selected based on their binding affinities, which ranged from − 11.6 kcal/mol to − 8.6 kcal/mol, coupled with low inhibition constants (0.005–7.590 μM) and favourable intermolecular interactions with key amino acid residues in the ATP-binding site. Cross-docking was performed to confirm selectivity against the JAK2 protein, and c-DFT analyses assessed inhibitor efficacy. The top lead compounds underwent a 300 ns MD analysis, revealing compounds L1 and L3 to exhibit favourable drug-likeness and robust ADMET profiles. The overall computational investigation demonstrated that these lead compounds serve as potent and selective inhibitors of JAK2.

Graphical abstract

Keywords: Computational Chemistry; Molecular Modelling; Molecular Target Identification; Protein-Ligand Interactions; Small Molecules; Virtual Drug Screening; Colon cancer; JAK2; Virtual screening; Molecular docking; DFT; MD simulation

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-025-04127-z

Chemical Papers 79 (8) 5319–5334 (2025)