Trichomonas vaginalis is a protozoan parasite that causes trichomoniasis, a sexually transmitted disease which may lead to harmful complications. Current treatment regimens rely on metronidazole or related 5-nitroimidazole compounds. However, strains resistant to these drugs are becoming more prevalent. Nucleoside ribohydrolase inhibitors represent a promising novel treatment strategy since the parasite requires nucleoside salvage pathways for its survival. Fragment screening of the uridine-specific nucleoside ribohydrolase (UNH) identified ligand-efficient scaffolds to serve as medicinal chemistry starting points for drug design. These compounds, and related analogs with the best potency for UNH, have been subjected to a combination of molecular modeling and parasitology studies. Molecular docking protocols with Autodock Vina and Chimera were established to dock compounds, analyze the active site binding interactions, and suggest chemical modifications that might improve binding. Docking calculations resulted in binding energies ranging between -6.5 to -11.5 kcal/mol for fragment scaffolds, synthesized compounds, and proposed compounds. Chimera was used to visualize docking results and identify key interactions between ligands and the UNH active site. For the parasitology studies, metronidazole-sensitive strain B7RC2 (ATCC 50167) of T. vaginalis was cultured anaerobically in TYM Diamond’s media supplemented with iron, penicillin, and streptomycin at 37°C. Cell viability after 24 hours of treatment was measured using hemocytometer counting. Compounds were prepared as 25 mM DMSO stock solutions and tested initially at 100 mM using DMSO and metronidazole as vehicle and positive controls, respectively. Active compounds were then tested in a dose-dependent fashion to determine antitrichomonal IC50 values. Compounds with the best combination of docking scores and T. vaginalis activity were then prioritized for guiding the design of compounds to be synthesized. It is expected that this process will simultaneously optimize antitrichomonal activity and enzyme inhibition resulting in compounds with nM activity in both assays.

Concerted use of molecular modeling and parasitology to guide design of novel Trichomonas vaginalis nucleoside ribohydrolase inhibitors

ACS Spring 2022

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