Identification of Novel Inhibitors of <i>Leishmania donovani</i> γ-Glutamylcysteine Synthetase Using Structure-Based Virtual Screening, Docking, Molecular Dynamics Simulation, and in Vitro Studies

Agnihotri, Pragati; Mishra, Arjun K.; Mishra, Shikha; Sirohi, Vijay Kumar; Sahasrabuddhe, Amogh A.; Pratap, J. Venkatesh

doi:10.1021/acs.jcim.6b00642

Cited by 25 publications

(18 citation statements)

References 38 publications

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“…To date, no commercial vaccines or specific therapies are available for EBOV. However, various studies have been reported that explain the comprehensive development of vaccines, small‐molecule inhibitors, and repurposed Food and Drug Administration (FDA) approved drugs against Ebola . Table provides an overview of anti‐EBOV compounds and their level of efficacy, reported in either IC 50 or EC 50 , in vitro assays against EBOV, clinical status, and observational studies.…”

Section: Introductionmentioning

confidence: 99%

Perspectives towards antiviral drug discovery against Ebola virus

Mirza

Vanmeert

Ali

et al. 2019

Journal of Medical Virology

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Ebola virus disease (EVD), caused by Ebola viruses, resulted in more than 11 500 deaths according to a recent 2018 WHO report. With mortality rates up to 90%, it is nowadays one of the most deadly infectious diseases. However, no Food and Drug Administration‐approved Ebola drugs or vaccines are available yet with the mainstay of therapy being supportive care. The high fatality rate and absence of effective treatment or vaccination make Ebola virus a category‐A biothreat pathogen. Fortunately, a series of investigational countermeasures have been developed to control and prevent this global threat. This review summarizes the recent therapeutic advances and ongoing research progress from research and development to clinical trials in the development of small‐molecule antiviral drugs, small‐interference RNA molecules, phosphorodiamidate morpholino oligomers, full‐length monoclonal antibodies, and vaccines. Moreover, difficulties are highlighted in the search for effective countermeasures against EVD with additional focus on the interplay between available in silico prediction methods and their evidenced potential in antiviral drug discovery.

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Section: Introductionmentioning

confidence: 99%

Perspectives towards antiviral drug discovery against Ebola virus

Mirza

Vanmeert

Ali

et al. 2019

Journal of Medical Virology

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“…However, including the docking pose of BSO would be a great addition to the work, as it would work as a positive control of the model and throw some light on what molecular determinants should be retained if an optimization of its toxicity would be carried in the future. The five ligands were successfully validated in vitro , four compounds had better enzymatic inhibition than BSO, dissociation constants comparable to it, and leishmanicidal activity, three of them having negligible toxicity in human cell lines (Agnihotri et al ., 2017). These results are a clear example of following in parallel the binding affinity and the ADME/Tox properties, and how information obtained from the predicted models could be of use for further lead optimization.…”

Section: Vs Applied To Trypanosomatid-caused Diseasesmentioning

confidence: 99%

Computational approaches for drug discovery against trypanosomatid-caused diseases

et al. 2020

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During three decades, only about 20 new drugs have been developed for malaria, tuberculosis and all neglected tropical diseases (NTDs). This critical situation was reached because NTDs represent only 10% of health research investments; however, they comprise about 90% of the global disease burden. Computational simulations applied in virtual screening (VS) strategies are very efficient tools to identify pharmacologically active compounds or new indications for drugs already administered for other diseases. One of the advantages of this approach is the low time-consuming and low-budget first stage, which filters for testing experimentally a group of candidate compounds with high chances of binding to the target and present trypanocidal activity. In this work, we review the most common VS strategies that have been used for the identification of new drugs with special emphasis on those applied to trypanosomiasis and leishmaniasis. Computational simulations based on the selected protein targets or their ligands are explained, including the method selection criteria, examples of successful VS campaigns applied to NTDs, a list of validated molecular targets for drug development and repositioned drugs for trypanosomatid-caused diseases. Thereby, here we present the state-of-the-art of VS and drug repurposing to conclude pointing out the future perspectives in the field.

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“…É uma proteína essencial da via biossintética da tripanotiona que catalisa a ligação ATPdependente de L-cisteína a L-glutamato, formando γ-glutamilcisteína. 28 A Leishmania requer pteridinas reduzidas (pterinas e folatos) para a biossíntese de ácidos nucleicos e proteínas e, portanto, captam a biopterina ou folato das células do seu hospedeiro. Estes dois compostos sofrem duas reduções sucessivas para gerar a forma ativa de tetra-hidrofolato.…”

Section: Periódicounclassified

“…8,23,24 Em alguns deles, foram realizados ainda estudos pré-clinicos com roedores, 50 bem como testes enzimáticos. 28 De forma complementar aos estudos de docagem molecular, é de grande importância a avaliação da dinâmica molecular, técnica computacional que avalia a evolução temporal das posições e velocidades dos átomos do complexo proteína-ligante e que vem sendo utilizada por alguns autores. 28,54,55 Os estudos de docagem molecular, associados aos estudos in vitro e in vivo, vem demonstrando ser uma etapa essencial no planejamento de novos fármacos.…”

Section: Periódicounclassified

“…28 De forma complementar aos estudos de docagem molecular, é de grande importância a avaliação da dinâmica molecular, técnica computacional que avalia a evolução temporal das posições e velocidades dos átomos do complexo proteína-ligante e que vem sendo utilizada por alguns autores. 28,54,55 Os estudos de docagem molecular, associados aos estudos in vitro e in vivo, vem demonstrando ser uma etapa essencial no planejamento de novos fármacos. Novos alvos moleculares essenciais ao metabolismo e sobrevivência do parasita vem sendo descobertos.…”

Section: Periódicounclassified

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Prospecting Biochemical Targets for in silico Study for Antileishmania Chemotherapy

Figueiredo¹,

Figueiredo²,

Costa³

et al. 2018

Rev. Virtual Quim.

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The objective of this work is to carry out a prospection of docking molecular on biochemical targets of Leishmania sp. The scientific prospection was executed in May /2017 and based on the search for articles in the Virtual Health Library (VHL). In 2006-2017, 84 articles were selected from several countries, including India, Brazil and Mexico. In the classification of the Protein Data Bank (PDB), molecular targets were found belongs to oxidoreductases, hydrolases, transferases, isomerases, DNA, proteases, etc. The most important species of Leishmania sp. were L. major, L. donovani, L. infantum, L. amazonensis, etc. The 3 main molecular targets were found trypanothione reductase, pteridine reductase and topoisomerase I, besides various targets involved in the immune system, carbohydrate metabolism, ATP, nitrogen bases, amino acids, etc. It was possible to find the 3 most studied enzymes (trypanothione reductase -2JK6; pteridine reductase 1 -1E7W; topoisomerase I -2B9S) what play important biological functions in the parasites and important molecular targets in antileishmania therapy.

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Identification of Novel Inhibitors of Leishmania donovani γ-Glutamylcysteine Synthetase Using Structure-Based Virtual Screening, Docking, Molecular Dynamics Simulation, and in Vitro Studies

Cited by 25 publications

References 38 publications

Perspectives towards antiviral drug discovery against Ebola virus

Perspectives towards antiviral drug discovery against Ebola virus

Computational approaches for drug discovery against trypanosomatid-caused diseases

Prospecting Biochemical Targets for in silico Study for Antileishmania Chemotherapy

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