Unveiling six potent and highly selective antileishmanial agents via the open source compound collection ‘Pathogen Box’ against antimony-sensitive and -resistant Leishmania braziliensis

Silva, Juliano A. Souza; Tunes, Luiza; Coimbra, Roney Santos; Ascher, David B.; Pires, Douglas E V; Monte-Neto, Rubens L.

doi:10.1016/j.biopha.2020.111049

Cited by 9 publications

(3 citation statements)

References 57 publications

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“…Then, quantitative data acquired by the pkCSM tool were converted into binary data considering the reference values defined by the program. We also calculated a pkCSM score according to Souza Silva et al. (2021) , and an ADMET-score, based on 18 properties predicted by admetSAR 2.0, using a scoring function proposed by Guan et al.…”

Section: Methodsmentioning

confidence: 99%

Docking-Based Virtual Screening Enables Prioritizing Protein Kinase Inhibitors With In Vitro Phenotypic Activity Against Schistosoma mansoni

Moreira

Batista

Tavares

et al. 2022

Front. Cell. Infect. Microbiol.

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Schistosomiasis is a parasitic neglected disease with praziquantel (PZQ) utilized as the main drug for treatment, despite its low effectiveness against early stages of the worm. To aid in the search for new drugs to tackle schistosomiasis, computer-aided drug design has been proved a helpful tool to enhance the search and initial identification of schistosomicidal compounds, allowing fast and cost-efficient progress in drug discovery. The combination of high-throughput in silico data followed by in vitro phenotypic screening assays allows the assessment of a vast library of compounds with the potential to inhibit a single or even several biological targets in a more time- and cost-saving manner. Here, we describe the molecular docking for in silico screening of predicted homology models of five protein kinases (JNK, p38, ERK1, ERK2, and FES) of Schistosoma mansoni against approximately 85,000 molecules from the Managed Chemical Compounds Collection (MCCC) of the University of Nottingham (UK). We selected 169 molecules predicted to bind to SmERK1, SmERK2, SmFES, SmJNK, and/or Smp38 for in vitro screening assays using schistosomula and adult worms. In total, 89 (52.6%) molecules were considered active in at least one of the assays. This approach shows a much higher efficiency when compared to using only traditional high-throughput in vitro screening assays, where initial positive hits are retrieved from testing thousands of molecules. Additionally, when we focused on compound promiscuity over selectivity, we were able to efficiently detect active compounds that are predicted to target all kinases at the same time. This approach reinforces the concept of polypharmacology aiming for “one drug-multiple targets”. Moreover, at least 17 active compounds presented satisfactory drug-like properties score when compared to PZQ, which allows for optimization before further in vivo screening assays. In conclusion, our data support the use of computer-aided drug design methodologies in conjunction with high-throughput screening approach.

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Section: Methodsmentioning

confidence: 99%

Docking-Based Virtual Screening Enables Prioritizing Protein Kinase Inhibitors With In Vitro Phenotypic Activity Against Schistosoma mansoni

Moreira

Batista

Tavares

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Drug repositioning is an effective strategy to find new applications for existing drugs (Andrade-Neto et al, 2018;Silva et al, 2021). Thus, drugs and/or compounds that interact with different proteins involved in important metabolic pathways in Leishmania were searched.…”

Section: Chemotherapy and Antioxidant Defense Enzymesmentioning

confidence: 99%

Perspectives From Systems Biology to Improve Knowledge of Leishmania Drug Resistance

Horácio

Hickson

Murta

et al. 2021

Front. Cell. Infect. Microbiol.

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Neglected Tropical Diseases include a broad range of pathogens, hosts, and vectors, which represent evolving complex systems. Leishmaniasis, caused by different Leishmania species and transmitted to humans by sandflies, are among such diseases. Leishmania and other Trypanosomatidae display some peculiar features, which make them a complex system to study. Leishmaniasis chemotherapy is limited due to high toxicity of available drugs, long-term treatment protocols, and occurrence of drug resistant parasite strains. Systems biology studies the interactions and behavior of complex biological processes and may improve knowledge of Leishmania drug resistance. System-level studies to understand Leishmania biology have been challenging mainly because of its unusual molecular features. Networks integrating the biochemical and biological pathways involved in drug resistance have been reported in literature. Antioxidant defense enzymes have been identified as potential drug targets against leishmaniasis. These and other biomarkers might be studied from the perspective of systems biology and systems parasitology opening new frontiers for drug development and treatment of leishmaniasis and other diseases. Our main goals include: 1) Summarize current advances in Leishmania research focused on chemotherapy and drug resistance. 2) Share our viewpoint on the application of systems biology to Leishmania studies. 3) Provide insights and directions for future investigation.

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“…The rapid emergence and spread of resistant parasite strains has prompted the need for new intervention pathways and antileishmanial drugs. In this way, repurposing of approved drugs has become a very attractive strategy to tackle leishmaniases and is gaining supporters worldwide [ 1 , 7 , 8 ]. DNA topoisomerases (TOP) have garnered attention since their discovery by James Wang in 1971 [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan

et al. 2021

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Background The evolution of drug resistance is one of the biggest challenges in leishmaniasis and has prompted the need for new antileishmanial drugs. Repurposing of approved drugs is a faster and very attractive strategy that is gaining supporters worldwide. Different anticancer topoisomerase 1B (TOP1B) inhibitors have shown strong antileishmanial activity and promising selective indices, supporting the potential repurposing of these drugs. However, cancer cells and Leishmania share the ability to become rapidly resistant. The aim of this study was to complete a whole-genome exploration of the effects caused by exposure to topotecan in order to highlight the potential mechanisms deployed by Leishmania to favor its survival in the presence of a TOP1B inhibitor. Methods We used a combination of stepwise drug resistance selection, whole-genome sequencing, functional validation, and theoretical approaches to explore the propensity of and potential mechanisms deployed by three independent clones of L. infantum to resist the action of TOP1B inhibitor topotecan. Results We demonstrated that L. infantum is capable of becoming resistant to high concentrations of topotecan without impaired growth ability. No gene deletions or amplifications were identified from the next-generation sequencing data in any of the three resistant lines, ruling out the overexpression of efflux pumps as the preferred mechanism of topotecan resistance. We identified three different mutations in the large subunit of the leishmanial TOP1B (Top1BF187Y, Top1BG191A, and Top1BW232R). Overexpression of these mutated alleles in the wild-type background led to high levels of resistance to topotecan. Computational molecular dynamics simulations, in both covalent and non-covalent complexes, showed that these mutations have an effect on the arrangement of the catalytic pentad and on the interaction of these residues with surrounding amino acids and DNA. This altered architecture of the binding pocket results in decreased persistence of topotecan in the ternary complex. Conclusions This work helps elucidate the previously unclear potential mechanisms of topotecan resistance in Leishmania by mutations in the large subunit of TOP1B and provides a valuable clue for the design of improved inhibitors to combat resistance in both leishmaniasis and cancer. Our data highlights the importance of including drug resistance evaluation in drug discovery cascades. Graphical abstract

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Unveiling six potent and highly selective antileishmanial agents via the open source compound collection ‘Pathogen Box’ against antimony-sensitive and -resistant Leishmania braziliensis

Cited by 9 publications

References 57 publications

Docking-Based Virtual Screening Enables Prioritizing Protein Kinase Inhibitors With In Vitro Phenotypic Activity Against Schistosoma mansoni

Docking-Based Virtual Screening Enables Prioritizing Protein Kinase Inhibitors With In Vitro Phenotypic Activity Against Schistosoma mansoni

Perspectives From Systems Biology to Improve Knowledge of Leishmania Drug Resistance

Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan

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