Molecular modelling study to discover novel JAK2 signaling pathway inhibitor

Abstract

The JAK2/STAT signaling cascades facilitates receptor signals which is responsible for cell growth, survival and homeostasis. Ligand binding to JAKs causes phosphorylation other proteins known as STATs, which translocate to the nucleus and regulate transcription of several important proteins. Growth hormone, prolactin and γ-interferon known agonists of JAK STAT receptors, signal to the nucleus by a more direct manner than the receptor tyrosine kinases. Mutations in JAKs may be responsible for immunodeficiency and myeloproliferative disorders because of its important role in cytokine signaling and making the pathway a therapeutic target for various disease. The present study screened Zinc database to find novel JAK2 inhibitors using virtual high throughput screening techniques. Selection of compound for further study was on the basis of docking score, free energy and binding pattern of the compound. Molecular simulation and MM/GBSA free energy was evaluated for the binding interactions and the stability of docked conformations. Several parameters which determine protein ligand interaction like RMSD, RMSF, Rg and binding pattern were observed. Hydrogen bonds (Glu 930, 932 and Asp 994) after 150 ns simulation were observed between identified compound INC000096136346 and it was similar to known inhibitor ruxolitinib. MM/GBSA free energy was comparable to known inhibitor ruxolitinib. ZINC000096136346 qualify Lipinski’s rule of five, rule of three, WDI like rule and there is one violation in lead like rule.

Communicated by Ramaswamy H. Sarma

Keywords:

• JAK2
• virtual screening
• docking
• molecular dynamics simulation
• free energy

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

One of the author Amit Singh thanks Banaras Hindu University 42872 for financial support.