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.
Highlights
Carbon dioxide (CO2) is a product of many metabolic aerobic processes in different organisms
Trypanosoma cruzi carbonic anhydrase (TcCA) has been recently cloned and characterised by Pan et al.[24]. The three His residues coordinating the Zinc ion are conserved in the active site of TcCA, with the fourth coordination position occupied by a water molecule
There are 924 structures of CAs deposited in the Protein Data Bank (PDB)[75], but all of them have sequence identities lower than 30% with TcCA
Summary
Carbon dioxide (CO2) is a product of many metabolic aerobic processes in different organisms It has a relatively low solubility in water, but it reacts with this solvent (at the neutral pH) to produce bicarbonate anion and protons. Known as Chagas disease, is caused by the parasite Trypanosoma cruzi[21]. The therapeutic arsenal to treat Chagas is composed of only two drugs, benznidazole and nifurtimox[23]. They were discovered more than 40 years ago, and they are mostly active in the acute phase of the disease
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