Classifying natural products from plants, fungi or bacteria using the COCONUT database and machine learning

Capecchi, Alice; Reymond, Jean‐Louis

doi:10.1186/s13321-021-00559-3

Cited by 24 publications

(31 citation statements)

References 69 publications

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“…Of these, the majority are of plant origin (50%), followed by fungal (23%), bacterial (16%), Homo sapiens (2.5%), animal (2%), and marine (1.5%) origin. 34 The remaining 5% lack a superclass annotation, and it was annotated as "other". To define a lipidated subset among the 67 656 unique natural products, we selected those with an uninterrupted hydrocarbon chain of at least eight atoms.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Our analysis focused on the 67 656 COCONUT entries annotated with a taxonomical origin and a publication DOI. Of these, the majority are of plant origin (50%), followed by fungal (23%), bacterial (16%), Homo sapiens (2.5%), animal (2%), and marine (1.5%) origin . The remaining 5% lack a superclass annotation, and it was annotated as “other”.…”

Section: Resultsmentioning

confidence: 99%

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Medium-Chain Lipid Conjugation Facilitates Cell-Permeability and Bioactivity

et al. 2022

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The majority of bioactive molecules act on membrane proteins or intracellular targets and therefore needs to partition into or cross biological membranes. Natural products often exhibit lipid modifications to facilitate critical molecule–membrane interactions, and in many cases their bioactivity is markedly reduced upon removal of a lipid group. However, despite its importance in nature, lipid-conjugation of small molecules is not commonly used in chemical biology and medicinal chemistry, and the effect of such conjugation has not been systematically studied. To understand the composition of lipids found in natural products, we carried out a chemoinformatic characterization of the “natural product lipidome”. According to this analysis, lipidated natural products predominantly contain saturated medium-chain lipids (MCLs), which are significantly shorter than the long-chain lipids (LCLs) found in membranes and lipidated proteins. To study the usefulness of such modifications in probe design, we systematically explored the effect of lipid conjugation on five different small molecule chemotypes and find that permeability, cellular retention, subcellular localization, and bioactivity can be significantly modulated depending on the type of lipid tail used. We demonstrate that MCL conjugation can render molecules cell-permeable and modulate their bioactivity. With all explored chemotypes, MCL-conjugates consistently exhibited superior uptake or bioactivity compared to LCL-conjugates and either comparable or superior uptake or bioactivity to short-chain lipid (SCL)-conjugates. Together, our findings suggest that conjugation of small molecules with MCLs could be a powerful strategy for the design of probes and drugs.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Medium-Chain Lipid Conjugation Facilitates Cell-Permeability and Bioactivity

et al. 2022

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“…Since our main interest is to propose natural KDM4 inhibitors, we used the COlleCtion of Open Natural Products (COCONUT), which gathers 406,744 natural products from over 50 different databases, where nearly half the compounds come mainly from plants, fungi, bacteria, and to a lesser extent, from animal or marine origins ( Capecchi and Reymond, 2021 ; Sorokina et al, 2021 ). Most of these compounds ( Sorokina et al, 2021 ) have been used as traditional medicine in China, India (Ayurveda), Japan (Kampo), Korea, Mexico, among other countries ( Yuan et al, 2016 ; Gutiérrez-Rebolledo et al, 2017 ) and come from Asia, Africa, Brazil, and Mexico ( Sorokina et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic and Drug Discovery Analyses Reveal Natural Compounds Targeting the KDM4 Subfamily as Promising Adjuvant Treatments in Cancer

et al. 2022

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KDM4 proteins are a subfamily of histone demethylases that target the trimethylation of lysines 9 and 36 of histone H3, which are associated with transcriptional repression and elongation respectively. Their deregulation in cancer may lead to chromatin structure alteration and transcriptional defects that could promote malignancy. Despite that KDM4 proteins are promising drug targets in cancer therapy, only a few drugs have been described as inhibitors of these enzymes, while studies on natural compounds as possible inhibitors are still needed. Natural compounds are a major source of biologically active substances and many are known to target epigenetic processes such as DNA methylation and histone deacetylation, making them a rich source for the discovery of new histone demethylase inhibitors. Here, using transcriptomic analyses we determined that the KDM4 family is deregulated and associated with a poor prognosis in multiple neoplastic tissues. Also, by molecular docking and molecular dynamics approaches, we screened the COCONUT database to search for inhibitors of natural origin compared to FDA-approved drugs and DrugBank databases. We found that molecules from natural products presented the best scores in the FRED docking analysis. Molecules with sugars, aromatic rings, and the presence of OH or O- groups favor the interaction with the active site of KDM4 subfamily proteins. Finally, we integrated a protein-protein interaction network to correlate data from transcriptomic analysis and docking screenings to propose FDA-approved drugs that could be used as multitarget therapies or in combination with the potential natural inhibitors of KDM4 enzymes. This study highlights the relevance of the KDM4 family in cancer and proposes natural compounds that could be used as potential therapies.

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“…Of these, the majority are of plant origin (50%), followed by fungal (23%), bacterial (16%), homo sapiens (2.5%), animal (2%), and marine (1.5%) origin. 32 The remaining 5% lack a superclass annotation, and it was annotated as "other". To define a lipidated subset among the 67,656 unique natural products, we selected those with an uninterrupted hydrocarbon chain of at least eight atoms.…”

Section: Chemoinformatic Characterization Of the 'Natural Product Lipidome'mentioning

confidence: 99%

Medium-Length Lipids Facilitate Cell-Permeability and Bioactivity

Capecchi

Hinnah²,

Petit-Jacques

et al. 2021

Preprint

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The majority of bioactive molecules act on membrane proteins or intracellular targets and therefore needs to partition into or cross biological membranes. Natural products often exhibit lipid modifications to facilitate critical molecule-membrane interactions and in many cases their bioactivity is markedly reduced upon removal of a lipid group. However, despite its importance in nature, lipid-conjugation of small molecules is not commonly used in chemical biology and medicinal chemistry, and the effect of such conjugation has not been systematically studied. To understand the composition of lipids found in natural products, we carried out a chemoinformatic characterization of the ‘natural product lipidome’. According to this analysis, lipidated natural products predominantly contain saturated linear medium-length lipids, which are significantly shorter than those found in membranes and lipidated proteins. To study the usefulness of such modifications in probe design, we systematically explored the effect of lipid conjugation on five different small molecule chemotypes and find that permeability, cellular retention, subcellular localization, and bioactivity can be significantly modulated depending on the type of lipid tail used. We demonstrate that medium-length lipid tails can render impermeable molecules cell-permeable and switch on their bioactivity. Saturated medium-length lipids (e.g. C10) are found to be ideal for the bioactivity of small molecules in mammalian cells, while saturated long-chain lipids (e.g. C18) often significantly reduce bioavailability and activity. Together, our findings suggest that conjugation of small molecules with medium-length lipids could be a powerful strategy for the design of probes and drugs.

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Classifying natural products from plants, fungi or bacteria using the COCONUT database and machine learning

Cited by 24 publications

References 69 publications

Medium-Chain Lipid Conjugation Facilitates Cell-Permeability and Bioactivity

Medium-Chain Lipid Conjugation Facilitates Cell-Permeability and Bioactivity

Transcriptomic and Drug Discovery Analyses Reveal Natural Compounds Targeting the KDM4 Subfamily as Promising Adjuvant Treatments in Cancer

Medium-Length Lipids Facilitate Cell-Permeability and Bioactivity

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