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In Silico Insights into the Mechanism of Action of Epoxy-α-Lapachone and Epoxymethyl-Lawsone in Leishmania spp.

ABSTRACT: Epoxy-α-lapachone (Lap) and Epoxymethyl-lawsone (Law) are oxiranes derived from Lapachol and have been shown to be promising drugs for Leishmaniases treatment. Although, it is known the action spectrum of both compounds affect the Leishmania spp. multiplication, there are gaps in the molecular binding details of target enzymes related to the parasite's physiology. Molecular docking assays simulations were performed using DockThor server to predict the preferred orientation of both compounds to form stable complexes with key enzymes of metabolic pathway, electron transport chain, and lipids metabolism of Leishmania spp. This study showed the hit rates of both compounds interacting with lanosterol C-14 demethylase (-8.4 kcal/mol to -7.4 kcal/mol), cytochrome c (-10.2 kcal/mol to -8.8 kcal/mol), and glyceraldehyde-3-phosphate dehydrogenase (-8.5 kcal/mol to -7.5 kcal/mol) according to Leishmania spp. and assessed compounds. The set of molecular evidence reinforces the potential of both compounds as multi-target drugs for interrupt the network interactions between parasite enzymes, which can lead to a better efficacy of drugs for the treatment of leishmaniases.

SUBMITTER: Peixoto JF

PROVIDER: S-EPMC8229338 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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In Silico Insights into the Mechanism of Action of Epoxy-α-Lapachone and Epoxymethyl-Lawsone in <i>Leishmania</i> spp.

Peixoto Juliana Figueiredo JF Oliveira Adriane da Silva ADS Monteiro Patrícia Queiroz PQ Gonçalves-Oliveira Luiz Filipe LF Andrade-Neto Valter Viana VV Ferreira Vitor Francisco VF Souza-Silva Franklin F Alves Carlos Roberto CR

Molecules (Basel, Switzerland) 20210610 12

Epoxy-α-lapachone (Lap) and Epoxymethyl-lawsone (Law) are oxiranes derived from Lapachol and have been shown to be promising drugs for Leishmaniases treatment. Although, it is known the action spectrum of both compounds affect the <i>Leishmania</i> spp. multiplication, there are gaps in the molecular binding details of target enzymes related to the parasite's physiology. Molecular docking assays simulations were performed using DockThor server to predict the preferred orientation of both compoun ...[more]

PMID: 34200517

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Project description:Leishmaniasis is a group of neglected infectious diseases, with approximately 1. 3 million new cases each year, for which the available therapies have serious limitations. Therefore, it is extremely important to apply efficient and low-cost methods capable of selecting the best therapeutic targets to speed up the development of new therapies against those diseases. Thus, we propose the use of integrated computational methods capable of evaluating the druggability of the predicted proteomes of Leishmania braziliensis and Leishmania infantum, species responsible for the different clinical manifestations of leishmaniasis in Brazil. The protein members of those proteomes were assessed based on their structural, chemical, and functional contexts applying methods that integrate data on molecular function, biological processes, subcellular localization, drug binding sites, druggability, and gene expression. These data were compared to those extracted from already known drug targets (BindingDB targets), which made it possible to evaluate Leishmania proteomes for their biological relevance and treatability. Through this methodology, we identified more than 100 proteins of each Leishmania species with druggability characteristics, and potential interaction with available drugs. Among those, 31 and 37 proteins of L. braziliensis and L. infantum, respectively, have never been tested as drug targets, and they have shown evidence of gene expression in the evolutionary stage of pharmacological interest. Also, some of those Leishmania targets showed an alignment similarity of <50% when compared to the human proteome, making these proteins pharmacologically attractive, as they present a reduced risk of side effects. The methodology used in this study also allowed the evaluation of opportunities for the repurposing of compounds as anti-leishmaniasis drugs, inferring potential interaction between Leishmania proteins and ~1,000 compounds, of which only 15 have already been tested as a treatment for leishmaniasis. Besides, a list of potential Leishmania targets to be tested using drugs described at BindingDB, such as the potential interaction of the DEAD box RNA helicase, TRYR, and PEPCK proteins with the Staurosporine compound, was made available to the public.

Dataset Information

In Silico Insights into the Mechanism of Action of Epoxy-α-Lapachone and Epoxymethyl-Lawsone in Leishmania spp.

Publications

In Silico Insights into the Mechanism of Action of Epoxy-α-Lapachone and Epoxymethyl-Lawsone in <i>Leishmania</i> spp.

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