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A Novel Triose Phosphate Isomerase Inhibitor With Dual Trypanosomicidal Activity was Identified Using Artificial
Elena Aguilera1, Rachel Ramos2, Aram Davtyan3
1Grupo de Química Orgánica Medicinal, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
Abstract:
Chagas disease and leishmaniasis are neglected protozoan diseases recognized by the World Health Organization as major public health problems. These diseases affect millions of people worldwide, yet effective treatments remain unavailable. Triosephosphate isomerase (TIM), a glycolytic enzyme that exhibits high catalytic efficiency for the isomerization of glyceraldehyde-3-phosphate and dihydroxyacetone-phosphate exclusively in its dimeric form, was subjected to virtual screening. Using a deep neural network for structure-based drug design that predicts binding affinity between small molecules and proteins of known structure, 12.5 million commercially available compounds were screened. From this, 82 compounds were selected for in vitro evaluation. Six compounds inhibited TIM from Trypanosoma cruzi, three of which exhibited anti-T. cruzi activity. Eight compounds demonstrated activity against the parasites T. cruzi and Leishmania infantum. Two compounds showed similar potency against both parasites: 3-(1-acetyl-5-(4-bromophenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-hydroxy-6-methyl-2H-pyran-2-one (IC50 = 16 ± 3 μM) and 3-[(4-bromophenyl)sulfanyl]-1-(3-nitrophenyl)propan-1-one (IC50 = 12 ± 1 μM). These compounds exhibit favorable selectivity and toxicological profiles, as well as in vivo activity, indicating their potential for future drug development.
Insights
New drug candidates show promise for treating neglected protozoan diseases like Chagas disease and leishmaniasis. Researchers identified compounds targeting the triosephosphate isomerase (TIM) enzyme, offering potential new therapeutic avenues.
Area of Science:
- Biochemistry
- Drug Discovery
- Parasitology
Background:
- Chagas disease and leishmaniasis are neglected protozoan diseases with significant global health impact.
- Current treatments for these diseases are limited and often toxic.
- Triosephosphate isomerase (TIM) is a crucial enzyme in parasite metabolism and a potential drug target.
Purpose of the Study:
- To identify novel small molecules that inhibit Trypanosoma cruzi and Leishmania infantum triosephosphate isomerase (TIM).
- To evaluate the anti-parasitic activity and drug-like properties of identified inhibitors.
Main Methods:
- Virtual screening of 12.5 million compounds using a deep neural network for structure-based drug design.
- In vitro evaluation of selected compounds for TIM inhibition and anti-parasitic activity.
- Assessment of compound selectivity and toxicological profiles.
Main Results:
- Six compounds inhibited TIM from Trypanosoma cruzi, with three showing anti-T. cruzi activity.
- Eight compounds demonstrated activity against both T. cruzi and Leishmania infantum.
- Two compounds exhibited potent activity against both parasites, with favorable selectivity and toxicological profiles.
Conclusions:
- The identified compounds represent promising leads for the development of new drugs against Chagas disease and leishmaniasis.
- Targeting parasite TIM is a viable strategy for anti-parasitic drug discovery.
- Further development of these compounds could lead to effective treatments for these neglected diseases.
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