Exploring molecular interactions of potential inhibitors against the spleen tyrosine kinase implicated in autoimmune disorders via virtual screening and molecular dynamics simulations

ABSTRACT

The spleen tyrosine kinase (Syk) plays a pivotal role in immune cells’ signal transduction mechanism. While fostamatinib, an FDA-approved Syk inhibitor, is currently used to treat immune thrombocytopenia, the search for improved Syk-targeted medications to treat autoimmune diseases is still underway. Herein, we screened 38,493 compounds against Syk and selected eight leads based on the docking score and ADMET properties, and performed 3$\times$200 ns long molecular dynamics simulations of the apo and Syk-ligand complexes. We considered R406, the active component of fostamatinib, as a control. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations demonstrated the lead1 ($\mathrm{\Delta }{G}_{\mathrm{b}\mathrm{i}\mathrm{n}\mathrm{d}}$ = -30.35 kcal/mol) exhibited a similar binding free energy as the control ($\mathrm{\Delta }{G}_{\mathrm{b}\mathrm{i}\mathrm{n}\mathrm{d}}$= −29.82 kcal/mol). The Syk stabilizing effect of lead1 was also indicated in its network features, sampling space, and residual correlation motion analysis. We further generated 100 structural analogues of lead1 using deep learning, and one of the analogues displayed a better binding free energy ($\mathrm{\Delta }{G}_{\mathrm{b}\mathrm{i}\mathrm{n}\mathrm{d}}$= −47.58 kcal/mol) compared to the control or lead1, facilitated by more favourable van der Waals interactions and lesser binding-opposing net polar forces. This analogue may be further exploited to develop effective therapeutics against Syk-associated diseases after validation in vitro and in vivo.

KEYWORDS:

• Spleen tyrosine kinase
• autoimmune disease
• virtual screening
• molecular dynamics
• free energy

Acknowledgements

SS thanks the Ministry of Education, Govt. of India, for providing a doctoral fellowship under the JRF scheme. MFS would like to thank the Department of Science and Technology, Govt. of India, for providing a doctoral fellowship under the INSPIRE fellowship scheme (DST/INSPIRE Fellowship/2017/IF170145). SK would like to thank the University Grants Commission for providing a doctoral fellowship under the JRF scheme.

Disclosure statement

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

Data availability statement

The data supporting this study’s findings are available from the corresponding author (PK) upon reasonable request.

Ethics statement

There is no human or animal experiment in this study.

Supplementary material

Supplemental data for this article can be accessed at: https://doi.org/10.1080/1062936X.2023.2266364.

Additional information

Funding

This work was partially supported by the Department of Science and Technology, Govt. of India [grant number DST/NSM/R&D_HPC_Applications/2021/03.18 and SR/FST/LS-I/2020/621].