High-throughput approaches for genotoxicity testing in drug development: recent advances

Ranganatha, Roopasri; Chakravarthy, Sridhara; Sukumaran, Sunil K.

doi:10.2147/ijhts.s70362

Cited by 8 publications

(4 citation statements)

References 34 publications

(37 reference statements)

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“…To identify mutagenicity of a substance, the AMES toxicity test uses multiple strains of Salmonella typhimurium bacteria with a gene mutation in the production of histidine [41]. Mitragynine tested negative in the AMES toxicity test, suggesting that it is nonmutagenic.…”

Section: Adme and Toxicity Studiesmentioning

confidence: 99%

Repurposing Mitragynine as Anti-SARS-CoV-2 Agent Evidenced by In Silico Predictive Approach

Tap

Zakaria

Majid

et al. 2022

Mal. J. Fund. Appl. Sci.

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The ongoing coronavirus disease-2019 (COVID-19) catastrophe calls for the development of therapeutic approaches to combat the disease. Therefore, an in silico study was conducted to evaluate druggability capacity of mitragynine, a natural indole alkaloid compound, using adsorption, distribution, metabolism, and excretion (ADME) prediction and molecular docking simulation to the region binding domain of severe acute respiratory coronavirus 2 (SARS-CoV-2 RBD). The pharmacodynamics of mitragynine were evaluated for its druggability using SwissADME software, and molecular docking simulation was performed using using AutoDock software, using SARS-CoV-2 RBD (PDB ID: 6M0J) as the protein target retrieved from Protein Data Bank (PDB). ADME predicted that this compound has excellent druggability, transport properties, and pharmacokinetics, following Lipinski’s rule of five. Mitragynine is also nonmutagenic based on the AMES toxicity test. No PAINS alert was observed and synthetic acceptability score was 4.49, suggesting a moderately synthesised compound. Through the molecular docking approach, mitragynine successfully docked the binding site of SARS-CoV-2 RBD with a binding energy of -6.3kcal/mol and formed hydrogen bonds with the residue N501, which is one of the residues at the binding site of RBD. These findings, together with other therapeutic qualities of mitragynine warrant for more research into molecular dynamics, in vitro, and in vivo studies in COVID-19 therapy.

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Section: Adme and Toxicity Studiesmentioning

confidence: 99%

Repurposing Mitragynine as Anti-SARS-CoV-2 Agent Evidenced by In Silico Predictive Approach

Tap

Zakaria

Majid

et al. 2022

Mal. J. Fund. Appl. Sci.

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“…More and more industries integrate sustainability and safety to their research and development, which implies to consider the use of a safe-by-design approach (Schwarz-Plaschg et al 2017). In this respect, high throughput screening (HTS) genotoxicity testing can present lots of advantages (Sukumaran et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Exploring graphene-based materials’ genotoxicity: inputs of a screening method

et al. 2021

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Graphene-based materials (GBMs) are promising nanomaterials, and several innovations depend on their use. However, the assessment of their potential hazard must be carefully explored before entering any market. GBMs are indeed well-known to induce various biological impacts, including oxidative stress, which can potentially lead to DNA damage. Genotoxicity is a major endpoint for hazard assessment and has been explored for GBMs, but the available literature shows conflicting results. In this study, we assessed the genotoxicity of 13 various GBMs, one carbon black and one amorphous silica through a DNA damage response assay (using a human respiratory cell model, BEAS-2B).Concurrently, oxidative stress was assessed through a ROS production quantification (DCFH-DA assay using a murine macrophage model, RAW 264.7). We also performed a full physicochemical characterization of our samples to explore potential structureactivity relationships involving genotoxicity. We observed that surface oxidation appears linked to genotoxicity response and were able to distinguish several groups within our studied GBMs showing different genotoxicity results. Our findings highlight the necessity to individually consider each nanoform of GBMs since the tested samples showed various results and modes of action. We propose this study as a genotoxicity assessment using a high-throughput screening method and suggest few hypotheses concerning the genotoxicity mode of action of GBMs.

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“…The effect of a genotoxic compound may vary from the intervention in the various proteins that are involved in the replication process and maintenance of chromosomal activity. A genotoxic compound may also possess a property that causes mutations and breaks in the deoxyribonucleic acid (DNA) structure (Ranganatha et al, 2016). Many of the discovered drugs used to treat cancer (Gwozdzinski and Lichota, 2018;Swift and Golsteyn, 2014), microbial infection (Brambilla et al, 2012;Galdiero et al, 2016), wound (Mattana et al, 2014) and inflammation (Brambilla and Martelli, 2009) have demonstrated genotoxic properties.…”

Section: Introductionmentioning

confidence: 99%

Mitodepressive and Genotoxic Potential of Crude Body Wall and Cuvierian Tubule Extracts of Mani-mani (Pearsonothuria graeffei Semper) on Root Meristems of Onion (Allium cepa L.)

Torres,

Malaya

2021

MJST

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The need to discover novel natural products has resulted in several explorations in the marine environment. The biological compounds from aquatic resources can boost effort on drug development and may promote species conservation. In this study, the mitodepressive and genotoxic properties of the extracts obtained from Pearsonothuria graeffei – a widely distributed and poorly explored sea cucumber species – were evaluated using the Allium test. The sea cucumber body wall and cuvierian tubule crude methanol, ethyl acetate and n-hexane extracts were found to have potential genotoxic properties at concentrations of 500, 1,000 and 1,500 μg mL-1. A significant (p < 0.05) growth inhibition in both length and the number of roots was exhibited at higher concentrations (1,000 and 1,500 μg mL-1) of the crude extracts similar to the control mutagen. The 1,000 μg mL-1 of cuvierian tubule methanol extract resulted in higher general toxicity in terms of root length inhibition than the control mutagen. A significantly lower mitotic index was exhibited in the crude body wall methanol extract at 500 μg mL-1 concentration. Also, a higher percent chromosomal aberration (p < 0.05) was observed in onions treated with all concentrations of crude body wall ethyl acetate and n-hexane extracts, and 500 μg mL-1 of the crude cuvierian tubule methanol and n-hexane extracts. In conclusion, the crude extracts of P. graeffei have mitodepressive and genotoxic properties, which are potential sources of bioactive compounds necessary for the development of treatment for some serious human diseases like cancer.

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High-throughput approaches for genotoxicity testing in drug development: recent advances

Cited by 8 publications

References 34 publications

Repurposing Mitragynine as Anti-SARS-CoV-2 Agent Evidenced by In Silico Predictive Approach

Repurposing Mitragynine as Anti-SARS-CoV-2 Agent Evidenced by In Silico Predictive Approach

Exploring graphene-based materials’ genotoxicity: inputs of a screening method

Mitodepressive and Genotoxic Potential of Crude Body Wall and Cuvierian Tubule Extracts of Mani-mani (Pearsonothuria graeffei Semper) on Root Meristems of Onion (Allium cepa L.)

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