| AI-Powered In Silico Drug Discovery Against Borrelia Infection: Targeting an Emerging Tick-Borne Threat Through Next-Generation SYK Inhibitors |
| Paper ID : 1120-IPCA5 (R2) |
| Authors |
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Elina Khanehzar1, Fatemeh Shams1, Zakkyeh Telmadarraiy2, Faezeh Faghihi3, Amirsajad Jafari *4 11. Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran 2. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran 21. Department of Medical Entomology and Vector Control, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran 2. Rahyan Novin Danesh (RND) University, Sari, Mazandaran, Iran 31. Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran 2. Immunogenetics Research Center, Mazandaran University of Medical Sciences, Sari, Iran 41. Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
2. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran |
| Abstract |
| Borrelia infection is an emerging public health threat in Iran, particularly in the humid subtropical regions of the Caspian Sea (Mazandaran, Guilan, and Golestan provinces), where Ixodes ricinus ticks serve as the primary vector. With Borrelia infection rates reaching 10% in local tick populations and increasing human cases, the disease remains underdiagnosed due to overlapping symptoms with other tick-borne pathogens like Anaplasma and Babesia, as well as a lack of effective treatments for persistent infections. Beyond I. ricinus, other ticks such as Rhipicephalus annulatus and Ornithodoros tholozani transmit Borrelia theileri and B. persica (causing relapsing fever), while the role of R. sanguineus and Hyalomma spp. as potential vectors remains uncertain. Tick saliva further complicates the disease by suppressing host immunity, enabling Borrelia dissemination and chronic infection. To address these challenges, this study proposes an AI-driven approach to design novel inhibitors targeting spleen tyrosine kinase (SYK), a key mediator of inflammatory signaling hijacked by Borrelia. By disrupting both bacterial survival and tick-induced immunomodulation, this strategy aims to provide a dual therapeutic solution, urgently needed in Iran’s Lyme-endemic zones where traditional diagnostics and treatments fall short. LLMs (DeepSeek & Grok) generated 100 innovative drug-like molecules targeting SYK. The top 10 candidates were filtered using SwissADME for optimal pharmacokinetics and Lipinski compliance. Molecular docking (AutoDock Vina in PyRx) evaluated binding interactions against SYK (PDB ID: 4YJR), benchmarking performance against the clinical SYK inhibitor Fostamatinib. Two AI-designed compounds outperformed Fostamatinib, achieving superior binding affinities (–9.9 & –9.7 kcal/mol vs. –8 kcal/mol) and demonstrating unprecedented SYK inhibition potential. These candidates also exhibited ideal drug-likeness, making them promising for Borrelia infection therapy. Our AI-optimized SYK inhibitors show high binding affinity and drug-likeness, offering a dual-action strategy against Borrelia infections such as Lyme disease in Iran. With Ixodes ticks expanding due to climate change and deforestation, these compounds could address critical gaps in managing Borrelia infections, particularly in high-risk areas like Mazandaran and Guilan. Future research should validate these inhibitors in models incorporating Iranian Ixodes tick saliva to assess efficacy against local Borrelia strains. Integrating these therapies with tick-control measures, such as acaricide-treated livestock and public awareness campaigns, could reduce Borrelia transmission in endemic regions. This approach not only advances Borrelia infection treatment but also provides a framework for combating other emerging tick-borne diseases in Iran. |
| Keywords |
| AI drug design, LLMs, Borrelia infection, SYK inhibitors, computational pharmacology |
| Status: Abstract Accepted |
