ABSTRACT
In this work, we combined molecular modeling, computational docking and in vitro analysis to explore the antileishmanial effect of some resveratrol analogs (ResAn), focusing on their pro-oxidant effect. The molecular target was the trypanothione reductase of Leishmania braziliensis (LbTryR), an essential component of the antioxidant defenses in trypanosomatid parasites. Three-dimensional structures of LbTryR were modeled and molecular docking studies of ResAn1-5 compounds showed the following affinity: ResAn1 > ResAn2 > ResAn4 > ResAn5 > ResAn3. Positive correlation was observed between these compounds' affinity to the LbTryR and the IC50 values against Leishmania sp (ResAn1 < ResAn2 < ResAn4), which allows for TryR being considered an important target for them. As the compound ResAn1 showed the best antileishmanial activity, and docking studies showed its high affinity for NADP binding site (NS) of TryR, plus having been able to induce ROS production in L. braziliensis promastigotes treated, ResAn1 probably occupies NS interfering in the electron transfer processes responsible for the catalytic reaction. The in silico prediction of ADMET properties suggests that ResAn1 may be a promising drug candidate with properties to cross biological membranes and high gastrointestinal absorption, not violating Lipinski's rules. Ultimately, the antileishmanial effect of ResAn can be associated with a pro-oxidant effect which, in turn, can be exploited as an antimicrobial agent. Communicated by Ramaswamy H. Sarma.
Subject(s)
Antiprotozoal Agents/pharmacology , Gene Expression Regulation, Enzymologic/drug effects , Leishmania braziliensis/drug effects , Leishmania braziliensis/enzymology , Leishmaniasis/drug therapy , NADH, NADPH Oxidoreductases/metabolism , Resveratrol/chemistry , Animals , Antioxidants/chemistry , Antioxidants/pharmacology , Antiprotozoal Agents/chemistry , Binding Sites , Leishmaniasis/parasitology , Macrophages/drug effects , Macrophages/enzymology , Macrophages/parasitology , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Docking Simulation , Molecular Structure , NADH, NADPH Oxidoreductases/chemistry , Protein Conformation , Protozoan Proteins/chemistry , Protozoan Proteins/metabolism , Reactive Oxygen Species/metabolism , Resveratrol/pharmacology , Structure-Activity RelationshipABSTRACT
In this study, we evaluated the inâ vitro and inâ vivo schistosomicidal activities of chalcones against Schistosoma mansoni worms. In vitro assays revealed that chalcones 1 and 3 were the most active compounds, without affecting significantly mammalian cells. Confocal laser scanning microscopy and scanning electron microscopy studies revealed reduction on the numbers of tubercles and morphological alterations in the tegument of S. mansoni worms after inâ vitro incubation with chalcones 1 and 3. In a mouse model of schistosomiasis, the oral treatment (400â mg/kg) with chalcone 1 or 3 significantly caused a total worm burden reduction in mice. Chalcone 1 showed significant inhibition of the S. mansoni ATP diphosphohydrolase activity, which was corroborated by molecular docking studies. The results suggested that chalcones could be explored as lead compounds with antischistosomal properties.