Abstract
Trypanosoma cruzi carbonic anhydrase (TcCA) has recently emerged as an interesting target for the design of new compounds to treat Chagas disease. In this study we report the results of a structure-based virtual screening campaign to identify novel and selective TcCA inhibitors. The combination of properly validated computational methodologies such as comparative modelling, molecular dynamics and docking simulations allowed us to find high potency hits, with KI values in the nanomolar range. The compounds also showed trypanocidal effects against T. cruzi epimastigotes and trypomastigotes. All the candidates are selective for inhibiting TcCA over the human isoform CA II, which is encouraging in terms of possible therapeutic safety and efficacy.
Keywords:
Chagas; acesulphame; carbonic anhydrase; sodium cyclamate; sulphamides; virtual screening.
MeSH terms
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Carbonic Anhydrase Inhibitors / chemical synthesis
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Carbonic Anhydrase Inhibitors / chemistry
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Carbonic Anhydrase Inhibitors / pharmacology*
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Carbonic Anhydrases / metabolism*
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Chagas Disease / drug therapy*
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Chagas Disease / metabolism
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Cyclamates / chemical synthesis
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Cyclamates / chemistry
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Cyclamates / pharmacology*
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Dose-Response Relationship, Drug
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Drug Evaluation, Preclinical
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Humans
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Models, Molecular
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Molecular Structure
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Parasitic Sensitivity Tests
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Structure-Activity Relationship
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Trypanocidal Agents / chemical synthesis
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Trypanocidal Agents / chemistry
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Trypanocidal Agents / pharmacology*
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Trypanosoma cruzi / drug effects
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Trypanosoma cruzi / enzymology
Substances
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Carbonic Anhydrase Inhibitors
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Cyclamates
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Trypanocidal Agents
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Carbonic Anhydrases
Grants and funding
This research was supported in part through grants from Agencia de Promoción Científica y Tecnológica [PICT 2013-0520], CONICET, and Universidad Nacional de La Plata, Argentina.