Identification of natural product-based effective inhibitors of spleen tyrosine kinase (SYK) through virtual screening and molecular dynamics simulation approaches

Abstract

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase that plays an essential role in signal transduction across different cell types. In the context of allergy and autoimmune disorders, it is a crucial regulator of immune receptor signaling in inflammatory cells such as B cells, mast cells, macrophages, and neutrophils. Developing SYK kinase inhibitors has gained significant interest for potential therapeutic applications in neurological and cancer-related conditions. The clinical use of the most advanced SYK inhibitor, Fostamatinib, has been limited due to its unwanted side effects. Thus, a more targeted approach to SYK inhibition would provide a more comprehensive treatment window. In this study, we used a virtual screening approach to identify potential SYK inhibitors from natural compounds from the IMPPAT database. We identified two compounds, Isolysergic acid and Michelanugine, which showed strong affinity and specificity for the SYK binding pocket. All-atom molecular dynamics (MD) simulations were also performed to explore the stability, conformational changes, and interaction mechanism of SYK in complexes with the identified compounds. The identified compounds might have the potential to be developed into promising SYK inhibitors for the treatment of various diseases, including autoimmune disorders, cancer, and inflammatory diseases. This work aims to identify potential phytochemicals to develop a new protein kinase inhibitor for treating advanced malignancies by providing an updated understanding of the role of SYK.

Communicated by Ramaswamy H. Sarma

Keywords:

• Spleen tyrosine kinase
• non-receptor tyrosine kinases
• MD simulation
• drug discovery
• phytochemicals

Disclosure statement

There is no conflict of interest to declare.

Authors’ contributions

Tufail Ali: Conceptualization, methodology, software, validation; Farah Anjum: formal analysis, investigation, resources, funding acquisition, project administration, Arunabh Choudhury: methodology, software, writing—original draft preparation, Amal Adnan Ashour: data curation, software, visualization, writing—original draft preparation, Alaa Shafie: investigation, resources, writing—review and editing, project administration, Abdulraheem Almalki: visualization, resources, supervision, funding acquisition, Taj Mohammad: Conceptualization, methodology, writing—review and editing, Md. Imtaiyaz Hassan: formal analysis, investigation, Project administration. All authors have read and agreed to the published version of the manuscript.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The researchers would like to acknowledge Deanship of Scientific Research, Taif University, for funding this work.