Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

High-throughput inhibitor screening and molecular dynamics simulation studies against Human JAK2

Rawabi Zahed^1,2 , Adel M Abuzenadah^3,4, Shazi Shakil^3,4,5, Adeel G Chaudhary^2,3,5

¹Department of Biology, Faculty of Sciences; ²Center of Innovation in Personalized Medicine; ³Department of Medical Laboratory Sciences; ⁴King Fahd Medical Research Center; ⁵Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.

For correspondence:- Rawabi Zahed Email: rzzahed@kau.edu.sa

Received: 25 September 2023 Accepted: 12 May 2025 Published: 31 May 2025

Citation: Zahed R, Abuzenadah AM, Shakil S, Chaudhary AG. High-throughput inhibitor screening and molecular dynamics simulation studies against Human JAK2. Trop J Pharm Res 2025; 24(5):599-605 doi: https://dx.doi.org/10.4314/tjpr.v24i5.4

© 2025 The authors.
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Abstract

Purpose: To investigate the lead molecule for inhibition of JAK2 using high-throughput screening and molecular dynamics simulation.

Methods: The MCULE database was used to screen 5 million ligands in a structure-based mode. The ligand hits were ranked according to VINA scores. Further filtration was achieved by approaches like MCULE-Toxicity Checker, Zero-RO5-Violation-Check, synthetic accessibility and overall pharmacokinetic features. Stability of the JAK2-inhibitor-complex was confirmed by molecular dynamics simulation of 120 ns, which used the AMBER14 force field in YASARA Structure-21.8.27. W.64.

Results: The top molecule, 4-pyrimidinamine, 2,6-dimethyl-5-(2,4,5-trimethylpyrido (2,3-d) pyrimidin-7-yl), demonstrated strong binding with JAK2 involving 17 amino acid residues, 16 of which overlapped with the reference (PDB: 3JY9). It successfully passed all screening tests. The RMSD-time plot indicated that equilibrium was reached around 20 ns. Throughout the simulation from 20 to 120 ns, the backbone RMSD fluctuations remained within a narrow range of 1.0 – 1.7 Å.

Conclusion: The ligand, 4-pyrimidinamine, 2,6-dimethyl-5-(2,4,5-trimethylpyrido (2,3-d) pyrimidin-7-yl), meets the ADMET criteria. Also, an extended 120 ns Molecular Dynamics Simulation confirms the feasibility of the 'JAK2-Top ligand' complex. This ligand is a promising lead for designing inhibitors against JAK2 and should be further evaluated in future laboratory experiments

Keywords: JAK2, High throughput virtual screening, Molecular Dynamics Simulation, Versatile therapeutic target