Trichomoniasis is a non-viral sexually transmitted disease caused by infection with the protozoan parasite Trichomonas vaginalis. In recent years the parasite has evolved increasing resistance to its current treatment with 5-nitroimidazole drugs. T. vaginalis is incapable of de novo synthesis of purine and pyrimidine rings, and thus the enzymes used in salvage pathways of these nucleosides are targets for new drug therapies. We hypothesize that targeting the purine-specific adenosine/guanosine nucleoside hydrolase (AGNH) by inhibiting the active site will likely eliminate or reduce parasite viability. The primary objective of the work described here is to use the fragment inhibitor N-(4-fluorophenyl)-4,5-dihydro-1H-imidazol-2-amine as the starting point for computational design of more potent compounds. This fragment has an IC50 value of 1.9 mM. The structure of the fragment bound to AGNH determined by X-ray crystallography was used to identify vectors for adding new chemical substituents. One potential vector would provide for additional hydrophobic interactions, while another would provide for potential interactions with the active site calcium ion. Computer modeling was used to predict the binding energy of each derivative. Compounds with good improvements in predicted binding energy and that also maintain ligand efficiency are prioritized for purchase or chemical synthesis. Compounds are then tested for activity against AGNH, and if potency improves, in parasite viability assays, with the project goal of identifying compounds with nM enzyme and antitrichomonal activities.

Computational design of trichomonas vaginalis purine nucleoside hydrolase inhibitors

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