Discovery of novel anti-inflammatory drug-like compounds by aligning in silico and in vivo screening: The nitroindazolinone chemotype

Marrero-Ponce, Yovani; Siverio-Mota, Dany; Gálvez-Llompart, María; Recio, M. C.; Giner, Rosa M.; García-Domènech, Ramón; Torrens, Francisco; Arán, Vicente J.; Cordero-Maldonado, María Lorena; Esguera, Camila V.; Witte, Peter de; Crawford, Alexander D.

doi:10.1016/j.ejmech.2011.07.053

Cited by 41 publications

(27 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using a zebrafish-based inflammation assay [22], we screened crude methanolic extracts from over 80 East African medicinal plants. The extract of Rhynchosia viscosa (Roth) DC.…”

Section: Resultsmentioning

confidence: 99%

Integration of Microfractionation, qNMR and Zebrafish Screening for the In Vivo Bioassay-Guided Isolation and Quantitative Bioactivity Analysis of Natural Products

et al. 2013

Self Cite

View full text Add to dashboard Cite

Natural products (NPs) are an attractive source of chemical diversity for small-molecule drug discovery. Several challenges nevertheless persist with respect to NP discovery, including the time and effort required for bioassay-guided isolation of bioactive NPs, and the limited biomedical relevance to date of in vitro bioassays used in this context. With regard to bioassays, zebrafish have recently emerged as an effective model system for chemical biology, allowing in vivo high-content screens that are compatible with microgram amounts of compound. For the deconvolution of the complex extracts into their individual constituents, recent progress has been achieved on several fronts as analytical techniques now enable the rapid microfractionation of extracts, and microflow NMR methods have developed to the point of allowing the identification of microgram amounts of NPs. Here we combine advanced analytical methods with high-content screening in zebrafish to create an integrated platform for microgram-scale, in vivo NP discovery. We use this platform for the bioassay-guided fractionation of an East African medicinal plant, Rhynchosia viscosa, resulting in the identification of both known and novel isoflavone derivatives with anti-angiogenic and anti-inflammatory activity. Quantitative microflow NMR is used both to determine the structure of bioactive compounds and to quantify them for direct dose-response experiments at the microgram scale. The key advantages of this approach are (1) the microgram scale at which both biological and analytical experiments can be performed, (2) the speed and the rationality of the bioassay-guided fractionation – generic for NP extracts of diverse origin – that requires only limited sample-specific optimization and (3) the use of microflow NMR for quantification, enabling the identification and dose-response experiments with only tens of micrograms of each compound. This study demonstrates that a complete in vivo bioassay-guided fractionation can be performed with only 20 mg of NP extract within a few days.

show abstract

“…Using a zebrafish-based inflammation assay [22], we screened crude methanolic extracts from over 80 East African medicinal plants. The extract of Rhynchosia viscosa (Roth) DC.…”

Section: Resultsmentioning

confidence: 99%

Integration of Microfractionation, qNMR and Zebrafish Screening for the In Vivo Bioassay-Guided Isolation and Quantitative Bioactivity Analysis of Natural Products

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently, our laboratory has established zebrafish as a biodiscovery platform to screen for novel active molecules, using zebrafish-based assays in particular for the bioassay-guided identification of drug-like natural products [19], [22], [31]–[33] and synthetic compounds [34]. Within this context, main objectives of this study were first to optimize an anti-inflammatory assay in non-transgenic zebrafish, to validate this improved assay with a panel of steroidal and non-steroidal anti-inflammatory drugs, and to determine the utility of this approach to analyze the anti-inflammatory activity of medicinal plants and their bio-active constituents.…”

Section: Discussionmentioning

confidence: 99%

Optimization and Pharmacological Validation of a Leukocyte Migration Assay in Zebrafish Larvae for the Rapid In Vivo Bioactivity Analysis of Anti-Inflammatory Secondary Metabolites

et al. 2013

Self Cite

View full text Add to dashboard Cite

Over the past decade, zebrafish (Danio rerio) have emerged as an attractive model for in vivo drug discovery. In this study, we explore the suitability of zebrafish larvae to rapidly evaluate the anti-inflammatory activity of natural products (NPs) and medicinal plants used in traditional medicine for the treatment of inflammatory disorders. First, we optimized a zebrafish assay for leukocyte migration. Inflammation was induced in four days post-fertilization (dpf) zebrafish larvae by tail transection and co-incubation with bacterial lipopolysaccharides (LPS), resulting in a robust recruitment of leukocytes to the zone of injury. Migrating zebrafish leukocytes were detected in situ by myeloperoxidase (MPO) staining, and anti-inflammatory activity was semi-quantitatively scored using a standardized scale of relative leukocyte migration (RLM). Pharmacological validation of this optimized assay was performed with a panel of anti-inflammatory drugs, demonstrating a concentration-responsive inhibition of leukocyte migration for both steroidal and non-steroidal anti-inflammatory drugs (SAIDs and NSAIDs). Subsequently, we evaluated the bioactivity of structurally diverse NPs with well-documented anti-inflammatory properties. Finally, we further used this zebrafish-based assay to quantify the anti-inflammatory activity in the aqueous and methanolic extracts of several medicinal plants. Our results indicate the suitability of this LPS-enhanced leukocyte migration assay in zebrafish larvae as a front-line screening platform in NP discovery, including for the bioassay-guided isolation of anti-inflammatory secondary metabolites from complex NP extracts.

show abstract

“…The research team has gained experience in discovering new drugs applying Molecular Topology, and has developed several models in the field of anti-inflammatory compounds [11–13]. …”

Section: Introductionmentioning

confidence: 99%

Modeling Natural Anti-Inflammatory Compounds by Molecular Topology

Gálvez-Llompart

Zanni

García-Domènech

2011

IJMS

View full text Add to dashboard Cite

One of the main pharmacological problems today in the treatment of chronic inflammation diseases consists of the fact that anti-inflammatory drugs usually exhibit side effects. The natural products offer a great hope in the identification of bioactive lead compounds and their development into drugs for treating inflammatory diseases. Computer-aided drug design has proved to be a very useful tool for discovering new drugs and, specifically, Molecular Topology has become a good technique for such a goal. A topological-mathematical model, obtained by linear discriminant analysis, has been developed for the search of new anti-inflammatory natural compounds. An external validation obtained with the remaining compounds (those not used in building up the model), has been carried out. Finally, a virtual screening on natural products was performed and 74 compounds showed actual anti-inflammatory activity. From them, 54 had been previously described as anti-inflammatory in the literature. This can be seen as a plus in the model validation and as a reinforcement of the role of Molecular Topology as an efficient tool for the discovery of new anti-inflammatory natural compounds.

show abstract

Discovery of novel anti-inflammatory drug-like compounds by aligning in silico and in vivo screening: The nitroindazolinone chemotype

Cited by 41 publications

References 85 publications

Integration of Microfractionation, qNMR and Zebrafish Screening for the In Vivo Bioassay-Guided Isolation and Quantitative Bioactivity Analysis of Natural Products

Integration of Microfractionation, qNMR and Zebrafish Screening for the In Vivo Bioassay-Guided Isolation and Quantitative Bioactivity Analysis of Natural Products

Optimization and Pharmacological Validation of a Leukocyte Migration Assay in Zebrafish Larvae for the Rapid In Vivo Bioactivity Analysis of Anti-Inflammatory Secondary Metabolites

Modeling Natural Anti-Inflammatory Compounds by Molecular Topology

Contact Info

Product

Resources

About