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Structural Similarities between Some Common Fluorophores Used in Biology, Marketed Drugs, Endogenous Metabolites, and Natural Products.

ABSTRACT: It is known that at least some fluorophores can act as 'surrogate' substrates for solute carriers (SLCs) involved in pharmaceutical drug uptake, and this promiscuity is taken to reflect at least a certain structural similarity. As part of a comprehensive study seeking the 'natural' substrates of 'orphan' transporters that also serve to take up pharmaceutical drugs into cells, we have noted that many drugs bear structural similarities to natural products. A cursory inspection of common fluorophores indicates that they too are surprisingly 'drug-like', and they also enter at least some cells. Some are also known to be substrates of efflux transporters. Consequently, we sought to assess the structural similarity of common fluorophores to marketed drugs, endogenous mammalian metabolites, and natural products. We used a set of some 150 fluorophores along with standard fingerprinting methods and the Tanimoto similarity metric. Results: The great majority of fluorophores tested exhibited significant similarity (Tanimoto similarity > 0.75) to at least one drug, as judged via descriptor properties (especially their aromaticity, for identifiable reasons that we explain), by molecular fingerprints, by visual inspection, and via the "quantitative estimate of drug likeness" technique. It is concluded that this set of fluorophores does overlap with a significant part of both the drug space and natural products space. Consequently, fluorophores do indeed offer a much wider opportunity than had possibly been realised to be used as surrogate uptake molecules in the competitive or trans-stimulation assay of membrane transporter activities.

SUBMITTER: O'Hagan S

PROVIDER: S-EPMC7700180 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Structural Similarities between Some Common Fluorophores Used in Biology, Marketed Drugs, Endogenous Metabolites, and Natural Products.

O'Hagan Steve S Kell Douglas B DB

Marine drugs 20201123 11

It is known that at least some fluorophores can act as 'surrogate' substrates for solute carriers (SLCs) involved in pharmaceutical drug uptake, and this promiscuity is taken to reflect at least a certain structural similarity. As part of a comprehensive study seeking the 'natural' substrates of 'orphan' transporters that also serve to take up pharmaceutical drugs into cells, we have noted that many drugs bear structural similarities to natural products. A cursory inspection of common fluorophor ...[more]

PMID: 33238416

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Project description:BackgroundPrevious studies compared the molecular similarity of marketed drugs and endogenous human metabolites (endogenites), using a series of fingerprint-type encodings, variously ranked and clustered using the Tanimoto (Jaccard) similarity coefficient (TS). Because this gives equal weight to all parts of the encoding (thence to different substructures in the molecule) it may not be optimal, since in many cases not all parts of the molecule will bind to their macromolecular targets. Unsupervised methods cannot alone uncover this. We here explore the kinds of differences that may be observed when the TS is replaced-in a manner more equivalent to semi-supervised learning-by variants of the asymmetric Tversky (TV) similarity, that includes α and β parameters.ResultsDramatic differences are observed in (i) the drug-endogenite similarity heatmaps, (ii) the cumulative "greatest similarity" curves, and (iii) the fraction of drugs with a Tversky similarity to a metabolite exceeding a given value when the Tversky α and β parameters are varied from their Tanimoto values. The same is true when the sum of the α and β parameters is varied. A clear trend toward increased endogenite-likeness of marketed drugs is observed when α or β adopt values nearer the extremes of their range, and when their sum is smaller. The kinds of molecules exhibiting the greatest similarity to two interrogating drug molecules (chlorpromazine and clozapine) also vary in both nature and the values of their similarity as α and β are varied. The same is true for the converse, when drugs are interrogated with an endogenite. The fraction of drugs with a Tversky similarity to a molecule in a library exceeding a given value depends on the contents of that library, and α and β may be "tuned" accordingly, in a semi-supervised manner. At some values of α and β drug discovery library candidates or natural products can "look" much more like (i.e., have a numerical similarity much closer to) drugs than do even endogenites.ConclusionsOverall, the Tversky similarity metrics provide a more useful range of examples of molecular similarity than does the simpler Tanimoto similarity, and help to draw attention to molecular similarities that would not be recognized if Tanimoto alone were used. Hence, the Tversky similarity metrics are likely to be of significant value in many general problems in cheminformatics.

Project description:ObjectivesMitigating carbon footprint of products used in resource-intensive areas such as surgical operating rooms will be important in achieving net zero carbon healthcare. The aim of this study was to evaluate the carbon footprint of products used within five common operations, and to identify the biggest contributors (hotspots).DesignA predominantly process-based carbon footprint analysis was conducted for products used in the five highest volume surgical operations performed in the National Health System in England.SettingThe carbon footprint inventory was based on direct observation of 6-10 operations/type, conducted across three sites within one NHS Foundation Trust in England.ParticipantsPatients undergoing primary elective carpal tunnel decompression, inguinal hernia repair, knee arthroplasty, laparoscopic cholecystectomy, tonsillectomy (March 2019 - January 2020).Main outcome measuresWe determined the carbon footprint of the products used in each of the five operations, alongside greatest contributors through analysis of individual products and of underpinning processes.ResultsThe mean average carbon footprint of products used for carpal tunnel decompression was 12.0 kg CO2e (carbon dioxide equivalents); 11.7 kg CO2e for inguinal hernia repair; 85.5 kg CO2e for knee arthroplasty; 20.3 kg CO2e for laparoscopic cholecystectomy; and 7.5 kg CO2e for tonsillectomy. Across the five operations, 23% of product types were responsible for ≥80% of the operation carbon footprint. Products with greatest carbon contribution for each operation type were the single-use hand drape (carpal tunnel decompression), single-use surgical gown (inguinal hernia repair), bone cement mix (knee arthroplasty), single-use clip applier (laparoscopic cholecystectomy) and single-use table drape (tonsillectomy). Mean average contribution from production of single-use items was 54%, decontamination of reusables 20%, waste disposal of single-use items 8%, production of packaging for single-use items 6% and linen laundering 6%.ConclusionsChange in practice and policy should be targeted towards those products making greatest contribution, and should include reducing single-use items and switching to reusables, alongside optimising processes for decontamination and waste disposal, modelled to reduce carbon footprint of these operations by 23%-42%.

Project description:Diabetes mellitus is a common effect of uncontrolled high blood sugar and it is associated with long-term damage, dysfunction, and failure of various organs. In the adult population, the global prevalence of diabetes has nearly doubled since 1980. Without effective prevention and management programs, the continuing significant rise in diabetes will have grave consequences on the health and lifespan of the world population, and also on the world economy. Supplements can be used to correct nutritional deficiencies or to maintain an adequate intake of certain nutrients. These are often used as treatments for diabetes, sometimes because they have lower costs, or are more accessible or "natural" compared to prescribed medications. Several vitamins, minerals, botanicals, and secondary metabolites have been reported to elicit beneficial effects in hypoglycemic actions in vivo and in vitro; however, the data remain conflicting. Many pharmaceuticals commonly used today are structurally derived from natural compounds from traditional medicinal plants. Botanicals that are most frequently used to help manage blood glucose include: bitter melon (Momordica charantia), fenugreek (Trigonella foenum graecum), gurmar (Gymnema sylvestre), ivy gourd (Coccinia indica), nopal (Opuntia spp.), ginseng, Russian tarragon (Artemisia dracunculus), cinnamon (Cinnamomum cassia), psyllium (Plantago ovata), and garlic (Allium sativum). In majority of the herbal products and secondary metabolites used in treating diabetes, the mechanisms of action involve regulation of insulin signaling pathways, translocation of GLUT-4 receptor and/or activation the PPAR?. Several flavonoids inhibit glucose absorption by inhibiting intestinal ?-amylase and ?-glucosidase. In-depth studies to validate the efficacies and safeties of extracts of these traditional medicinal plants are needed, and large, well designed, clinical studies need to be carried out before the use of such preparations can be recommended for treatment and/or prevention of diabetes. The main focus of this review is to describe what we know to date of the active compounds in these, along with their glucose-lowering mechanisms, which are either through insulin-mimicking activity or enhanced glucose uptake.

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Structural Similarities between Some Common Fluorophores Used in Biology, Marketed Drugs, Endogenous Metabolites, and Natural Products.

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Structural Similarities between Some Common Fluorophores Used in Biology, Marketed Drugs, Endogenous Metabolites, and Natural Products.

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