Development of a Novel Virtual Screening Cascade Protocol to Identify Potential Trypanothione Reductase Inhibitors

Perez-Pineiro, Rolando; Burgos, Asdrúbal; Jones, Deuan C.; Andrew, Lena C.; Rodríguez, Hortensia; Suárez, Margarita; Fairlamb, Alan H.; Wishart, David S.

doi:10.1021/jm801306g

Cited by 44 publications

(31 citation statements)

References 49 publications

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“…Additional evidence that the quinoline and 9-aminoacridine hits identified in the ELEC system are particularly good leads for further development is based on previous studies of these compounds as potential antimalarial compounds. Here it was shown that these relatively basic compounds with high LogP (lipophilicity) values favor their intracellular transport, which is responsible for the observed activity and selectivity (54)(55)(56)(57). Furthermore, it has been demonstrated that certain acridines (54,(58)(59)(60)(61) can inhibit DNA synthesis in Leishmania and/or Plasmodium, interfering with DNA transcription (topoisomerase II).…”

Section: Discussionmentioning

confidence: 99%

Development of anEx VivoLymph Node Explant Model for Identification of Novel Molecules Active against Leishmania major

Peniche

Osorio

Renslo

et al. 2014

Antimicrob Agents Chemother

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e Leishmaniasis is a vector-borne zoonotic infection affecting people in tropical and subtropical regions of the world. Current treatments for cutaneous leishmaniasis are difficult to administer, toxic, expensive, and limited in effectiveness and availability. Here we describe the development and application of a medium-throughput screening approach to identify new drug candidates for cutaneous leishmaniasis using an ex vivo lymph node explant culture (ELEC) derived from the draining lymph nodes of Leishmania major-infected mice. The ELEC supported intracellular amastigote proliferation and contained lymph node cell populations (and their secreted products) that enabled the testing of compounds within a system that mimicked the immunopathological environment of the infected host, which is known to profoundly influence parasite replication, killing, and drug efficacy. The activity of known antileishmanial drugs in the ELEC system was similar to the activity measured in peritoneal macrophages infected in vitro with L. major. Using the ELEC system, we screened a collection of 334 compounds, some of which we had demonstrated previously to be active against L. donovani, and identified 119 hits, 85% of which were confirmed to be active by determination of the 50% effective concentration (EC 50 ). We found 24 compounds (7%) that had an in vitro therapeutic index (IVTI; 50% cytotoxic/effective concentration [CC 50 ]/EC 50 ) > 100; 19 of the compounds had an EC 50 below 1 M. According to PubChem searchs, 17 of those compounds had not previously been reported to be active against Leishmania. We expect that this novel method will help to accelerate discovery of new drug candidates for treatment of cutaneous leishmaniasis.

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Section: Discussionmentioning

confidence: 99%

Development of anEx VivoLymph Node Explant Model for Identification of Novel Molecules Active against Leishmania major

Peniche

Osorio

Renslo

et al. 2014

Antimicrob Agents Chemother

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“…37,42,44 Alguns exemplos ilustram a aplicação destas técnicas na identificação de novos esqueletos químicos (scaffold hopping). 40,45 Etapas de LBVS Em geral, os métodos de LBVS se fundamentam em estudos de similaridade ou em modelos construídos a partir de conjuntos de ligantes e não ligantes. 40,43 As buscas por similaridade química envolvem a geração de impressões digitais moleculares para todas as moléculas das bases de dados.…”

Section: Triagem Virtual Baseada Na Estrutura Do Liganteunclassified

“…Outrossim, esta técnica é útil na análise prévia de grandes bases de dados, permitindo a geração de coleções dirigidas para avaliações posteriores, experimentais ou computacionais. 15,17,41,45 …”

Section: Figura 3 Estratégias De Lbvs: A) Lbvs Baseada Em Similaridaunclassified

“…Diversos exemplos de sucesso da aplicação da SBVS são descritos na literatura, demonstrando sua versatilidade, alto desempenho e grande utilidade em programas de descoberta fármacos. 12,25,45,[71][72][73] É interessante observar a rica variedade de classes químicas identificadas para uma igualmente abastada diversidade de alvos biológicos.…”

Section: Figura 4 Cuidados Na Preparação Do Receptor Para Sbvsunclassified

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Integração das técnicas de triagem virtual e triagem biológica automatizada em alta escala: oportunidades e desafios em P&D de fármacos

Ferreira¹,

Oliva²,

Andricopulo³

2011

Quím. Nova

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Recebido em 16/1/11; aceito em 2/6/11; publicado na web em 26/7/11 INTEGRATING VIRTUAL AND HIGH-THROUGHPUT SCREENING: OPPORTUNITIES AND CHALLENGES IN DRUG RESEARCH AND DEVELOPMENT. High-throughput screening (HTS) and virtual screening (VS) are useful methods employed in drug discovery, allowing the identification of promising hits for lead optimization. The efficiency of these approaches depends on a number of factors, such as the organization of high quality databases of compounds and the parameterization of essential components of the screen process. This brief review presents the basic principles of the HTS and VS methods, as well as a perspective of the utility and integration of these drug design approaches, highlighting current opportunities and future challenges in medicinal chemistry.Keywords: high-throughput screening; virtual screening; drug design. INTRODUÇÃOA descoberta de novos fármacos é um grande desafio para a indústria farmacêutica moderna. Os altos investimentos na área de pesquisa e desenvolvimento (P&D) contrastam com o número de novos medicamentos que têm chegado ao mercado nos últimos anos. 1 Este complexo panorama tem forçado a adoção de novas estratégias com o objetivo de aumentar a eficiência do processo de P&D, tendo como alicerces as inovações científicas, tecnológicas e empresariais.Considerando-se o expressivo número de alvos biológicos (proteínas alvo) promissores para o planejamento de fármacos, as técnicas de triagem biológica automatizada em alta escala (HTS -high throughput screening) e de triagem virtual (VS -virtual screening) têm ocupado papel de destaque entre as estratégias modernas exploradas na identificação de novas substâncias bioativas. Desde o seu surgimento, a HTS tem sido amplamente utilizada pela indústria farmacêutica, propiciando a avaliação de milhões de compostos contra proteínas alvo. Embora esta estratégia tenha despertado a esperança de uma revolução na descoberta de substâncias bioativas, em pouco tempo as suas limitações ficaram evidentes. 2 A ocorrência de um número elevado de falso-positivos, identificados inicialmente como hits (termo em inglês para designar um novo ligante ou composto bioativo) nos ensaios bioquímicos em alta escala pode ser destacada como um dos grandes problemas. 3 Os múltiplos modos de interação ou mecanismos de ação apresentados pelos diferentes hits selecionados podem também ser mencionados como outros importantes obstácu-los. 4 Além disso, o número possível de compostos com propriedades fármaco-similar (drug-like) 5 é várias ordens de magnitude maior do que o número de compostos que pode ser analisado nos processos de HTS. Portanto, o planejamento das bases de dados de compostos é essencial, sendo que fatores como propriedades moleculares e físico-químicas, ou ainda a diversidade química, devem ser considerados. [6][7][8] Com os notáveis avanços da biologia estrutural e a disponibilidade de recursos computacionais de alto desempenho, a VS surgiu como importante alternativa à HTS. A VS é um método in silico ("computacional") empre...

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“…Some experimental as well as in silico attempts have been made to identify inhibitors or subversive substrates for various molecular targets (Krauth-Siegel and Inhoff, 2003;Perez-Pineiro et al, 2009). The enzyme Tryparedoxin Peroxidase (Try P) of Leishmania braziliensis is a 199 amino acid enzyme with a molecular weight of approximately 22.5 kDa.…”

Section: Introductionmentioning

confidence: 99%

<i>IN SILICO</i> AND <i>IN VITRO</i> STUDIES: TRYPAREDOXIN PEROXIDASE INHIBITOR ACTIVITY OF METHOTREXATE FOR ANTILEISHMANIAL ACTIVITY

Gundampati¹

2013

American Journal of Infectious Diseases

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In order to understand the mechanism of molecular interactions at the active site of Tryparedoxin Peroxidase (Try P), homology modeling and docking studies were performed. We generated a Three-Dimensional (3D) model of target protein based on the Crystal structure of Leishmania Major Try PI (PDB ID: 3TUE) using modeler software. Docking analysis was carried out to study the effects of methotrexate on Tryparedoxin Peroxidase (Try P). Inhibition of the Tryparedoxin peroxidase interaction has become a new therapeutic strategy in treating leishmaniasis. Docking analysis was carried out to study the effects of methotrexate on Tryparedoxin Peroxidase (TryP). Tryparedoxin peroxidase of Trypanosomatidae family functions as antioxidant through their peroxidase and peroxynitrite reductase activities. The theoretical docking study, conducted on a sample previously reported for anti-cancer properties of Methotrexate at the binding site of 3D models of Tryparedoxin Peroxidase of Leishmania braziliensis (L. braziliensis Try P) examine interaction energy. Our studies indicate that Methotrexate displays potent activity against Try P with lowest binding energy and RMSD values to be -14.5879 Kcal/Mol and 2.0 A. The results of the present study clearly demonstrated the Tryparedoxin Peroxidase inhibitory activity by methotrexate in in silico docking analysis and in vitro assay which contributes towards understanding the mechanism of antileishmanial activity.

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Development of a Novel Virtual Screening Cascade Protocol to Identify Potential Trypanothione Reductase Inhibitors

Cited by 44 publications

References 49 publications

Development of anEx VivoLymph Node Explant Model for Identification of Novel Molecules Active against Leishmania major

Development of anEx VivoLymph Node Explant Model for Identification of Novel Molecules Active against Leishmania major

Integração das técnicas de triagem virtual e triagem biológica automatizada em alta escala: oportunidades e desafios em P&D de fármacos

<i>IN SILICO</i> AND <i>IN VITRO</i> STUDIES: TRYPAREDOXIN PEROXIDASE INHIBITOR ACTIVITY OF METHOTREXATE FOR ANTILEISHMANIAL ACTIVITY

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