Cell-Based Assays in Natural Product-Based Drug Discovery

Mukne, Alka; Momin, Misbah; Betkar, Parag; Rane, Tanvi; Valecha, Saurabh

doi:10.1007/978-981-15-8127-4_11

Cited by 3 publications

(4 citation statements)

References 105 publications

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“…We here employ whole cell binding assays for primary bioactive NP screening, a method expected to have higher sensitivity, throughput, and flexibility than the traditional phenotype-base screening methods. More importantly, these reporting cells simultaneously enrich active components from pre-binding NP mixtures as shown by the intracellular quantification studies of bioactive compounds by us and other researchers 16,17,18 . These assays thus allow facile active compound re-isolation from cells and detection by sensitive metabolomics analysis.…”

Section: Introductionmentioning

confidence: 86%

Bioactive Natural Product Discovery via Deuterium Adduct Bioactivity Screening

Zill¹,

Marinkovich³

et al. 2023

Preprint

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The discovery of bioactive natural products lies at the forefront of human medicine. The 20 continued discovery of these molecules is imperative in the fight against infection and disease. 21 While natural products have historically dominated the drug market, discovery in recent years has 22 slowed significantly, partly due to limitations in current discovery methodologies. This work 23 demonstrates a new workflow, Deuterium Adduct Bioactivity Screening (DABS), which pairs 24 untargeted isotope labeling with whole cell binding assays for bioactive natural product discovery. 25 DABS was validated and led to the discovery of a new isoprenyl guanidine alkaloid, zillamycin, 26 which showed anti-cancer and anti-microbial activities. DABS thus represents a new workflow to 27 accelerate discovery of natural products with a wide range of bioactive potential.

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Section: Introductionmentioning

confidence: 86%

Bioactive Natural Product Discovery via Deuterium Adduct Bioactivity Screening

Zill¹,

Marinkovich³

et al. 2023

Preprint

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“…Results revealed that compound (f) was the most active compound at the concentration of 16 μg/mL [36],…”

Section: • the Anti-tuberculosis Activity Of Compoundsmentioning

confidence: 98%

“…The series showed a similar activity spectrum as with the avirulent strain of Mtb (H37Ra). Compound (f) was most active in the series with MIC value16 µg/mL [36]. The compound (f) exhibited the best activity against the virulent M. tuberculosis (H37Rv) with MIC values of 16 µg/mL.…”

Section: • the Anti-tuberculosis Activity Of Compoundsmentioning

confidence: 98%

Antituberculosis Propensity of Synthetic Biscoumarin Derivatives: An In Silico and In Vitro Approach

Sheikh¹,

Bhat²,

Zareen³

et al. 2023

Preprint

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The concerning rise in emergence and prevalence of resistant strains to drugs of M. tuberculosis has ,the prompted researchers to look for new and effective treatments. With this motive, biscoumarins were identified as the lead molecules on a whole-cell-based screening of several less explored low molecular weight bioactive compounds against M. tuberculosis strains. Among the screened biscoumarins, the highest dock score derivatives were synthesized (a-h) using a programmable microwave synthesizer for better yields and reaction control. The synthesized derivatives were evaluated against H37Rv, H37Ra, M. smegmatis, an MDR surrogate model, and other bacterial strains for the structure-activity response. Assessment of the synthesized library against mycobacterial strains led to the identification of compounds (f and d) as lead anti-tuberculosis agents. Compounds (f and d) exhibited less toxicity against human cell lines. At the same time, it displayed enjoyable activity wherein MIC concentrations were observed to be 16- and 32 µg/mL against the susceptible H37Rv, and H37Ra strains of M. tuberculosis and MIC value of 128 µg/mL for M. smegmatis, respectively. For mechanistic insights and identification of drug binding targets, molecular docking and dynamic simulations were employed for a panel of 16 mycobacterial enzymes essential for mycobacterial growth and survival. These in silico studies revealed the DprE1 enzyme as a druggable target for the anti-tuberculosis activity of the selected biscoumarins derivatives. Further investigation is underway in our laboratory, leading to its development as an anti-tuberculosis drug (animal model studies).

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“…We here employ whole cell binding assays for primary bioactive NP screening, a method expected to have higher sensitivity, throughput, and flexibility than the traditional phenotype-based screening methods. More importantly, these reporting cells simultaneously enrich active components from pre-binding NP mixtures as shown by the intracellular quantification studies of bioactive compounds by us and other researchers. − These assays thus allow facile active compound re-isolation from cells and detection by sensitive metabolomics analysis. Doing so, any metabolite that has a specific target in reporting cells may be enriched and revealed, significantly enhancing the rate of active compound discovery.…”

Section: Introductionmentioning

confidence: 95%

Bioactive Natural Product Discovery via Deuterium Adduct Bioactivity Screening

Zill

Marinkovich

et al. 2023

ACS Chem. Biol.

View full text Add to dashboard Cite

The discovery of bioactive natural products lies at the forefront of human medicine. The continued discovery of these molecules is imperative in the fight against infection and disease. While natural products have historically dominated the drug market, discovery in recent years has slowed significantly, partly due to limitations in current discovery methodologies. This work demonstrates a new workflow, deuterium adduct bioactivity screening (DABS), which pairs untargeted isotope labeling with whole cell binding assays for bioactive natural product discovery. DABS was validated and led to the discovery of a new isoprenyl guanidine alkaloid, zillamycin, which showed anti-cancer and anti-microbial activities. DABS thus represents a new workflow to accelerate discovery of natural products with a wide range of bioactive potentials.

show abstract

Cell-Based Assays in Natural Product-Based Drug Discovery

Cited by 3 publications

References 105 publications

Bioactive Natural Product Discovery via Deuterium Adduct Bioactivity Screening

Bioactive Natural Product Discovery via Deuterium Adduct Bioactivity Screening

Antituberculosis Propensity of Synthetic Biscoumarin Derivatives: An In Silico and In Vitro Approach

Bioactive Natural Product Discovery via Deuterium Adduct Bioactivity Screening

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