The Calculation of Molecular Structural Similarity: Principles and Practice

Willett, Peter

doi:10.1002/minf.201400024

Cited by 104 publications

(88 citation statements)

References 89 publications

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“…[31][32][33] Extended connectivity fingerprints (ECFPs) can be used to analyze scaffold structures.I nE CFP_6, for instance,a ll structural features within the range of six bonds of each scaffold atom will be included in the fingerprint and can be interpreted as substructures. [34,35] Thus the fingerprint covers the complete molecular environment.…”

Section: Scaffolds and Scaffold Diversitymentioning

confidence: 99%

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

et al. 2016

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Scaffold diversity is a crucial feature of compound collections that has a huge impact on their success in biological screenings. The synthesis of highly complex and diverse scaffolds, which could be based on natural products, for example, is an arduous task that requires expertise in various aspects of organic synthesis and structural analysis. This challenge has been addressed by a number of synthesis designs, which employ natural products as a source of scaffold diversity, transform suitably designed common intermediates into various molecular frameworks, or entail highly concise synthetic routes to a number of distinct and complex scaffolds. In this Minireview, we highlight recent synthetic developments towards the construction of diverse and complex scaffolds and the application of the resulting compound collections in drug and probe discovery.

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Section: Scaffolds and Scaffold Diversitymentioning

confidence: 99%

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

et al. 2016

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“…Drugs that are also metabolites were removed from the list of drugs. Using the MACCS encoding [61], the similarity of each substance is compared via a KNIME workflow [62] using the Tanimoto similarity coefficient [63,64], whose values are encoded according to the colours indicated. Drugs and metabolites are clustered using an agglomerative clustering algorithm.…”

Section: Consequences Of the Fact That Individual Drugs Must And Do Umentioning

confidence: 99%

What would be the observable consequences if phospholipid bilayer diffusion of drugs into cells is negligible?

Kell

2015

Trends in Pharmacological Sciences

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For drug transport across (i.e., through) an intact biological membrane, two main routes are possible: drugs may cross (i) through the phospholipid bilayer portion of the membrane, and/or (ii) via proteinaceous pores or transporters. Perhaps surprisingly, there is in fact no direct scientific evidence that the first of these takes place at any significant rate because, in the experiments performed to date, it has neither been varied as an independent variable nor measured directly as a dependent variable. Using a standard hypothetico-deductive framework, I assess the intellectual and observable consequences of assuming that, for drugs, phospholipid bilayer diffusion is negligible - 'PBIN' - (i.e., may be neglected, relative to transporter-mediated transmembrane fluxes). Predictions and postdictions of the PBIN hypothesis are not refuted by available experimental evidence.

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“…Although more complex comparisons are occasionally used (e.g. [249][250][251]), strings are typically compared on the basis of the number of bits they have in common relative to the total, a true metric (between 0 and 1) known as the Jaccard or Tanimoto similarity. Although this is a continuous function, Tanimoto similarities above 0.8 are commonly found (i) to be resistant to the precise encoding used, and (ii) indeed to have broadly similar effects in most cases (review at [213]).…”

Section: The Importance Of Qsars (Quantitative Structure-activity Relmentioning

confidence: 99%

Control of metabolite efflux in microbial cell factories: current advances and future prospects

Kell¹

2018

Preprint

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The yield and ease of purification of biotechnological products are typically greatly enhanced if they can be secreted into the external medium. Although not universally appreciated, however, small molecule biotechnological products do not ‘float across’ the phospholipid bilayer portion of biological membranes, and thus they need transporters to assist their passage into the extramembrane and extracellular spaces. Some of these transporters may be reversible, equilibrative transporters that might more normally be used for uptake, while others may have an efflux directionality imposed on them via suitable energy coupling mechanisms. Despite the energetic costs of small molecule synthesis, natural evolution does in fact provide a number of mechanisms by which the secretion of such products can actually enhance fitness. Where available these provide useful starting points, and assaying for such activities is crucial. In particular, in a systems biology approach, we first need to identify such/suitable activities before we can seek to increase them. They may then be improved through promoter engineering, via manipulation of control elements, or by directed evolution of the transporter proteins themselves. Modern methods of synthetic biology provide enormous opportunities for all kinds of efflux transporter engineering; they are just beginning to be realised.

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The Calculation of Molecular Structural Similarity: Principles and Practice

Cited by 104 publications

References 89 publications

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

What would be the observable consequences if phospholipid bilayer diffusion of drugs into cells is negligible?

Control of metabolite efflux in microbial cell factories: current advances and future prospects

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