Finding inhibitors and deciphering inhibitor-induced conformational plasticity in the Janus kinase via multiscale simulations

ABSTRACT

The Janus kinase (JAK) is a master regulator of the JAK/STAT pathway. Dysregulation of this signalling cascade causes neuroinflammation and autoimmune disorders. Therefore, JAKs have been characterized as an attractive target for developing anti-inflammatory drugs. Nowadays, designing efficient, effective, and specific targeted therapeutics without being cytotoxic has gained interest. We performed the virtual screening of natural products in combination with pharmacological analyses. Subsequently, we performed molecular dynamics simulations to study the stability of the ligand-bound complexes and ligand-induced inactive conformations. Notably, inactive kinases display remarkable conformational plasticity; however, ligand-induced molecular mechanisms of these conformations are still poorly understood. Herein, we performed a free energy landscape analysis to explore the conformational plasticity of the JAK1 kinase. Leonurine, STOCK1N-68642, STOCK1N-82656, and STOCK1N-85809 bound JAK1 exhibited a smooth transition from an active (αC-in) to a completely inactive conformation (αC-out). Ligand binding induces disorders in the αC-helix. Molecular mechanics Poisson Boltzmann surface area (MM/PBSA) calculation suggested three phytochemicals, namely STOCK1N-68642, Epicatechin, and STOCK1N-98615, have higher binding affinity compared to other ligand molecules. The ligand-induced conformational plasticity revealed by our simulations differs significantly from the available crystal structures, which might help in designing allosteric drugs.

KEYWORDS:

• JAK/STAT
• virtual screening
• phytochemicals
• neuroinflammation
• molecular dynamics simulation
• conformational plasticity

Acknowledgements

The Department of Science and Technology (DST), Govt. of India (grant number DST/NSM/R&D_HPC_Applications/2021/03.18). MFS would like to thank DST, Gov. of India, for providing a doctoral fellowship under the INSPIRE Fellowship Scheme (DST/INSPIRE Fellowship/2017/IF170145).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data that support the findings of this study are available from the corresponding author (P. K.) upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed at: https://doi.org/10.1080/1062936X.2022.2145352

Additional information

Funding

This work was supported by the Department of Science and Technology, Ministry of Science and Technology [DST/NSM/R&D_HPC_Applications/2021/03.18]; Department of Science and Technology, Ministry of Science and Technology [DST/INSPIRE Fellowship/2017/IF170145,DST/NSM/R&D_HPC_Applications/2021/03.18].