Comparative proteomics and structure-based approach to unravel the therapeutic drug target of Theileria species.

Theileriosis, caused by protozoan parasites of genus Theileria, primarily affects both domestic and wild ruminants. It can lead to significant economic losses in livestock farming due to decreased productivity and high mortality rates in susceptible animals, while treatment measures are not cost-effective. Since most of mechanisms of this disease remain unknown, this study investigates the differences in the mode of pathogenesis between transforming and non-transforming groups through an in silico comparative proteomics approach to recognize the key players involved in host cell transformation. Although the major biological processes and molecular functions are almost conserved between the two groups, PEST-motif containing secretory proteins of SfiI, SVSP, and Tash-AT gene families were identified as important candidates with the potential to transform infected host cells. Several members of PEST-motif containing proteins possess signal peptides, nuclear localization signals, and trans-membrane helices, further supporting their potential to transform host cells. Additionally, structural analysis helped in the identification of a parasitic protein (SfiIp) from SfiI family as a plausible drug target. Virtual screening revealed FDA-approved drugs (i.e. atogepant and rimegepant) as promising compounds, showing the highest affinity for SfiIp during molecular docking. Further studies, including molecular dynamics simulation, principal component analysis, and free energy landscape, suggested that these drug molecules exhibit the stable interaction with protein. Therefore, our research could facilitate the identification and targeting of novel drug candidates that may be further implemented to recognize effective therapeutics against Theileria infections.