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

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.

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Structural similarities between some common fluorophores used in biology and marketed drugs, endogenous metabolites, and natural products

10.1101/834325 ◽

2019 ◽

Cited By ~ 2

Author(s):

Steve O’Hagan ◽

Douglas B. Kell

Keyword(s):

Natural Products ◽

Great Majority ◽

Structural Similarity ◽

Drug Uptake ◽

Pharmaceutical Drugs ◽

Significant Similarity ◽

Molecular Fingerprints ◽

Tanimoto Similarity ◽

Endogenous Metabolites ◽

Comprehensive Study

ABSTRACTBackgroundIt 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.ResultsThe 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 a significant part of both 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.

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Consensus rank orderings of molecular fingerprints illustrate the most genuine similarities between marketed drugs and small endogenous human metabolites, but highlight exogenous natural products as the most important ‘natural’ drug transporter substrates

ADMET & DMPK ◽

10.5599/admet.5.2.376 ◽

2017 ◽

Vol 5 (2) ◽

pp. 85 ◽

Cited By ~ 23

Author(s):

Steve O'Hagan ◽

Douglas Bruce Kell

Keyword(s):

Natural Products ◽

Natural Product ◽

Rank Order ◽

Great Majority ◽

Structural Similarity ◽

Molecular Fingerprint ◽

Molecular Fingerprints ◽

Small Molecule Drugs ◽

Tanimoto Similarity ◽

Drug Scaffolds

We compare several molecular fingerprint encodings for marketed, small molecule drugs, and assess how their rank order varies with the fingerprint in terms of the Tanimoto similarity to the most similar endogenous human metabolite as taken from Recon2. For the great majority of drugs, the rank order varies very greatly depending on the encoding used, and also somewhat when the Tanimoto similarity (TS) is replaced by the Tversky similarity. However, for a subset of such drugs, amounting to some 10 % of the set and a Tanimoto similarity of ~0.8 or greater, the similarity coefficient is relatively robust to the encoding used. This leads to a metric that, while arbitrary, suggests that a Tanimoto similarity of 0.75-0.8 or greater genuinely does imply a considerable structural similarity of two molecules in the drug-endogenite space. Although comparatively few (<10 % of) marketed drugs are, in this sense, robustly similar to an endogenite, there is often at least one encoding with which they are genuinely similar (e.g. TS > 0.75). This is referred to as the Take Your Pick Improved Cheminformatic Analytical Likeness or TYPICAL encoding, and on this basis some 66 % of drugs are within a TS of 0.75 to an endogenite.We next explicitly recognise that natural evolution will have selected for the ability to transport dietary substances, including plant, animal and microbial ‘secondary’ metabolites, that are of benefit to the host. These should also be explored in terms of their closeness to marketed drugs. We thus compared the TS of marketed drugs with the contents of various databases of natural products. When this is done, we find that some 80 % of marketed drugs are within a TS of 0.7 to a natural product, even using just the MACCS encoding. For patterned and TYPICAL encodings, 80 % and 98 % of drugs are within a TS of 0.8 to (an endogenite or) an exogenous natural product. This implies strongly that it is these exogeneous (dietary and medicinal) natural products that are more to be seen as the ‘natural’ substrates of drug transporters (as is recognised, for instance, for the solute carrier SLC22A4 and ergothioneine). This novel analysis casts an entirely different light on the kinds of natural molecules that are to be seen as most like marketed drugs, and hence potential transporter substrates, and further suggests that a renewed exploitation of natural products as drug scaffolds would be amply rewarded.

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Consensus rank orderings of molecular fingerprints illustrate the ‘most genuine’ similarities between marketed drugs and small endogenous human metabolites, but highlight exogenous natural products as the most important ‘natural’ drug transporter substrates

10.1101/110437 ◽

2017 ◽

Cited By ~ 2

Author(s):

Steve O’Hagan ◽

Douglas B. Kell

Keyword(s):

Natural Products ◽

Natural Product ◽

Rank Order ◽

Great Majority ◽

Structural Similarity ◽

Molecular Fingerprint ◽

Molecular Fingerprints ◽

Small Molecule Drugs ◽

Tanimoto Similarity ◽

Drug Scaffolds

AbstractWe compare several molecular fingerprint encodings for marketed, small molecule drugs, and assess how their rank order varies with the fingerprint in terms of the Tanimoto similarity to the most similar endogenous human metabolite as taken from Recon2. For the great majority of drugs, the rank order varies very greatly depending on the encoding used, and also somewhat when the Tanimoto similarity (TS) is replaced by the Tversky similarity. However, for a subset of such drugs, amounting to some 10% of the set and a Tanimoto similarity of ~0.8 or greater, the similarity coefficient is relatively robust to the encoding used. This leads to a metric that, while arbitrary, suggests that a Tanimoto similarity of 0.75-0.8 or greater genuinely does imply a considerable structural similarity of two molecules in the drug-endogenite space. Although comparatively few (<10% of) marketed drugs are, in this sense, robustly similar to an endogenite, there is often at least one encoding with which they are genuinely similar (e.g. TS > 0.75). This is referred to as the Take Your Pick Improved Cheminformatic Analytical Likeness or TYPICAL encoding, and on this basis some 66% of drugs are within a TS of 0.75 to an endogenite.We next explicitly recognise that natural evolution will have selected for the ability to transport dietary substances, including plant, animal and microbial ‘secondary’ metabolites, that are of benefit to the host. These should also be explored in terms of their closeness to marketed drugs. We thus compared the TS of marketed drugs with the contents of various databases of natural products. When this is done, we find that some 80% of marketed drugs are within a TS of 0.7 to a natural product, even using just the MACCS encoding. For patterned and TYPICAL encodings, 80% and 98% of drugs are within a TS of 0.8 to (an endogenite or) an exogenous natural product. This implies strongly that it is these exogeneous (dietary and medicinal) natural products that are more to be seen as the ‘natural’ substrates of drug transporters (as is recognised, for instance, for the solute carrier SLC22A4 and ergothioneine). This novel analysis casts an entirely different light on the kinds of natural molecules that are to be seen as most like marketed drugs, and hence potential transporter substrates, and further suggests that a renewed exploitation of natural products as drug scaffolds would be amply rewarded.

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Identification of molecular fingerprints of natural products for the inhibition of breast cancer resistance protein (BCRP)

Phytomedicine ◽

10.1016/j.phymed.2021.153523 ◽

2021 ◽

Vol 85 ◽

pp. 153523

Author(s):

Arghya Banik ◽

Kalyan Ghosh ◽

Umesh K. Patil ◽

Shovanlal Gayen

Keyword(s):

Breast Cancer ◽

Natural Products ◽

Breast Cancer Resistance Protein ◽

Cancer Resistance ◽

Molecular Fingerprints ◽

Resistance Protein

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Probing the promiscuity of ent-kaurene oxidases via combinatorial biosynthesis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1512096113 ◽

2016 ◽

Vol 113 (9) ◽

pp. 2526-2531 ◽

Cited By ~ 27

Author(s):

Sibongile Mafu ◽

Meirong Jia ◽

Jiachen Zi ◽

Dana Morrone ◽

Yisheng Wu ◽

...

Keyword(s):

Natural Products ◽

Metabolic Engineering ◽

Substrate Specificity ◽

Plant Hormone ◽

Structural Similarity ◽

Combinatorial Biosynthesis ◽

Underlying Structure ◽

Engineering System ◽

Insight Into

The substrate specificity of enzymes from natural products’ metabolism is a topic of considerable interest, with potential biotechnological use implicit in the discovery of promiscuous enzymes. However, such studies are often limited by the availability of substrates and authentic standards for identification of the resulting products. Here, a modular metabolic engineering system is used in a combinatorial biosynthetic approach toward alleviating this restriction. In particular, for studies of the multiply reactive cytochrome P450, ent-kaurene oxidase (KO), which is involved in production of the diterpenoid plant hormone gibberellin. Many, but not all, plants make a variety of related diterpenes, whose structural similarity to ent-kaurene makes them potential substrates for KO. Use of combinatorial biosynthesis enabled analysis of more than 20 such potential substrates, as well as structural characterization of 12 resulting unknown products, providing some insight into the underlying structure–function relationships. These results highlight the utility of this approach for investigating the substrate specificity of enzymes from complex natural products’ biosynthesis.

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BIOFACQUIM: A Mexican Compound Database of Natural Products

Biomolecules ◽

10.3390/biom9010031 ◽

2019 ◽

Vol 9 (1) ◽

pp. 31 ◽

Cited By ~ 20

Author(s):

B. Pilón-Jiménez ◽

Fernanda Saldívar-González ◽

Bárbara Díaz-Eufracio ◽

José Medina-Franco

Keyword(s):

Natural Products ◽

Drug Discovery ◽

Physicochemical Properties ◽

Chemical Space ◽

Structural Diversity ◽

Proof Of Concept ◽

Molecular Fingerprints ◽

The Public ◽

Compound Database

Compound databases of natural products have a major impact on drug discovery projects and other areas of research. The number of databases in the public domain with compounds with natural origins is increasing. Several countries, Brazil, France, Panama and, recently, Vietnam, have initiatives in place to construct and maintain compound databases that are representative of their diversity. In this proof-of-concept study, we discuss the first version of BIOFACQUIM, a novel compound database with natural products isolated and characterized in Mexico. We discuss its construction, curation, and a complete chemoinformatic characterization of the content and coverage in chemical space. The profile of physicochemical properties, scaffold content, and diversity, as well as structural diversity based on molecular fingerprints is reported. BIOFACQUIM is available for free.

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Incorporating Natural Products, Pharmaceutical Drugs, Self-Care and Digital/Mobile Health Technologies into Molecular-Behavioral Combination Therapies for Chronic Diseases

Current Clinical Pharmacology ◽

10.2174/1574884711666160603012237 ◽

2016 ◽

Vol 11 (2) ◽

pp. 128-145 ◽

Cited By ~ 10

Author(s):

Grzegorz Bulaj ◽

Margaret Ahern ◽

Alexis Kuhn ◽

Zachary Judkins ◽

Randy Bowen ◽

...

Keyword(s):

Natural Products ◽

Chronic Diseases ◽

Mobile Health ◽

Self Care ◽

Pharmaceutical Drugs ◽

Combination Therapies ◽

Health Technologies

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The Growth of a Mausoleum: The Pre-1600 Tombs and Brasses of St George's Chapel, Windsor

The Antiquaries Journal ◽

10.1017/s0003581500000901 ◽

2007 ◽

Vol 87 ◽

pp. 220-258

Author(s):

Nigel Saul

Keyword(s):

Great Majority ◽

Large Collection ◽

First Time ◽

Comprehensive Study

A comprehensive study is attempted of the pre-1600 monuments in St George's Chapel, Windsor Castle. Use is made for the first time of a key source, the set of plans of the chapel floors made by Henry Emlyn in 1789. These show the chapel once W have contained a large collection of monumental brasses. The plans are examined alongside the evidence of the extant indents in the chapel and cloister to reconstruct the original lay-out of the brasses. It is demonstrated that the great majority of the brasses commemorated the deans and canons who served the chapel. It is argued that the character of the chapel as a mausoleum changed after 1475, when Edward IV embarked on the building of the present fabric. From this time, the ranks of the commemorated expanded to include layfolk, particularly Knights of the Garter and men with royal connections, while, alongside the brasses, big sculpted monuments were commissioned in the side chapels of the building.

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Palladium-Catalyzed Formation of Substituted Tetrahydropyrans: Mechanistic Insights and Structural Revision of Natural Products

Synthesis ◽

10.1055/s-0037-1611708 ◽

2019 ◽

Vol 51 (07) ◽

pp. 1545-1560 ◽

Cited By ~ 4

Author(s):

Ronaldo Pilli ◽

Franco Della-Felice ◽

Francisco de Assis ◽

Ariel Sarotti

Keyword(s):

Natural Products ◽

Total Synthesis ◽

Palladium Catalyst ◽

Structural Revision ◽

Palladium Catalyzed ◽

Acyclic Precursor ◽

Comprehensive Study

A comprehensive study on the stereochemical outcome of palladium-catalyzed formation of 2,4,6-trisubstituted tetrahydropyrans through cyclization of the corresponding allylic acetates using both Pd(0) and Pd(II) catalysts is presented. We have found that the stereochemical outcome of this cyclization is dependent not only on the stereochemistry of the acyclic precursor but also on the nature of the palladium catalyst. These results were applied to the total synthesis of the putative structure of cryptoconcatone H. Experimental and computational DP4+ NMR results were used to assess the structures proposed for cryptoconcatones K and L.

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