Molecular and biochemical parasitology · 2025
Targeted inhibition of human Tankyrase-1 (TNKS1) by ZT-5483 exhibited anti-parasitic activity in Toxoplasma gondii: An in silico-based, high-throughput virtual screen and in vitro approach.
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Alraey Yasser
Аннотация
BACKGROUND AND AIM: Toxoplasmosis is considered one of the leading causes of mortality resulting from foodborne illness. This disease is caused by infection with the Toxoplasma gondii parasite. Given the serious side effects and recurrence of resistance, there is an unmet need to develop effective novel drugs with low toxicity against T. gondii. This study aims to identify novel anti-parasitic compounds targeting human Tankyrase-1 involved in T. gondii infection using bioinformatics and in vitro approaches.
METHODS: For lead identification, high-throughput virtual screening (HTVS) against the ChemBridge library was followed by Protein-Ligand Interaction Profiler, GROMACS, and GMX_MMPBSA techniques. Human TNKS1 (PARP5A) colorimetric assay was performed. The RH-2F strain of T. gondii tachyzoites that expressed beta-galactosidase was maintained in the human foreskin fibroblasts (HFFs) to determine the parasite growth-inhibitory efficacy of the lead candidate. MTT assay was used to detect the inhibition rate on host cell viability.
RESULTS: HTVS identified ZT-5483 with favorable binding affinities of 8.8 kcal/mol towards TNKS1. Molecular dynamic simulations demonstrated stable binding interactions for ZT-5483 and TNKS1 with Root Mean Square Deviation values around 0.04 nm. The ΔG binding calculation was -43.09 kcal/mol, favoring sturdy binding. ADME analysis supported favorable small-molecule characteristics. ZT-5483 dose responsively inhibited TNKS1 activity with an IC50 value of 140.8 nM. ZT-5483 suppressed the parasite growth with an IC50 value of 297.8 nM. The compound's cytotoxicity to HFF host cells (TD50 value) was determined to be 3354 nM. The in vitro toxicity index (TI) of ZT-5483 was 11.26 based on the IC50 and TD50 values.
CONCLUSION: Together, these findings suggest that ZT-5483 could be a potential novel candidate against T. gondii. However, further preclinical and pharmacological evaluations are warranted.
METHODS: For lead identification, high-throughput virtual screening (HTVS) against the ChemBridge library was followed by Protein-Ligand Interaction Profiler, GROMACS, and GMX_MMPBSA techniques. Human TNKS1 (PARP5A) colorimetric assay was performed. The RH-2F strain of T. gondii tachyzoites that expressed beta-galactosidase was maintained in the human foreskin fibroblasts (HFFs) to determine the parasite growth-inhibitory efficacy of the lead candidate. MTT assay was used to detect the inhibition rate on host cell viability.
RESULTS: HTVS identified ZT-5483 with favorable binding affinities of 8.8 kcal/mol towards TNKS1. Molecular dynamic simulations demonstrated stable binding interactions for ZT-5483 and TNKS1 with Root Mean Square Deviation values around 0.04 nm. The ΔG binding calculation was -43.09 kcal/mol, favoring sturdy binding. ADME analysis supported favorable small-molecule characteristics. ZT-5483 dose responsively inhibited TNKS1 activity with an IC50 value of 140.8 nM. ZT-5483 suppressed the parasite growth with an IC50 value of 297.8 nM. The compound's cytotoxicity to HFF host cells (TD50 value) was determined to be 3354 nM. The in vitro toxicity index (TI) of ZT-5483 was 11.26 based on the IC50 and TD50 values.
CONCLUSION: Together, these findings suggest that ZT-5483 could be a potential novel candidate against T. gondii. However, further preclinical and pharmacological evaluations are warranted.