Implications of the Dominant Role of Transporters in Drug Uptake by Cells (Supplementary Material)

Dobson, Paul D.; Lanthaler, Karin; Oliver, Stephen G.; Kell, Douglas B.

doi:10.2174/156802609787521616

Cited by 84 publications

(68 citation statements)

References 318 publications

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“…negative LogP) may also introduce issues as these polar molecules may have difficulty crossing cellular membranes unless specific transporting mechanisms are operating. [18][19][20] Some targets in, for example, anti-bacterial research, however, are thought to require more polar molecules to efficiently reach their sites of action.…”

Section: Properties Of Successful Hits and Drugsmentioning

confidence: 99%

Lead‐Oriented Synthesis: A New Opportunity for Synthetic Chemistry

2012

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The pharmaceutical industry remains solely reliant on synthetic chemistry methodology to prepare compounds for small-molecule drug discovery programmes. The importance of the physicochemical properties of these molecules in determining their success in drug development is now well understood but we present here data suggesting that much synthetic methodology is unintentionally predisposed to producing molecules with poorer drug-like properties. This bias may have ramifications to the early hit- and lead-finding phases of the drug discovery process when larger numbers of compounds from array techniques are prepared. To address this issue we describe for the first time the concept of lead-oriented synthesis and the opportunity for its adoption to increase the range and quality of molecules used to develop new medicines.

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Section: Properties Of Successful Hits and Drugsmentioning

confidence: 99%

Lead‐Oriented Synthesis: A New Opportunity for Synthetic Chemistry

2012

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“…Although our focus here is on microorganisms (and see [13]), the situation is also acute for mammalian transporters, as these underpin the distributions of xenobiotic pharmaceutical drugs within and between cells [8,[14][15][16][17][18][19][20].…”

Section: Of the Layout Of This Papermentioning

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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“…A second fundamental principle is that every protein is encoded by a string of DNA, the information being transmitted by mRNA. The exceptions to these general principles, are increasingly rare [15] and do not much compromise the stature of these principles as being fundamental. Biology does have general principles.…”

Section: Principles Of Systems Biologymentioning

confidence: 99%

Systems Biology: The elements and principles of Life

et al. 2009

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a b s t r a c tSystems Biology has a mission that puts it at odds with traditional paradigms of physics and molecular biology, such as the simplicity requested by Occam's razor and minimum energy/maximal efficiency. By referring to biochemical experiments on control and regulation, and on flux balancing in yeast, we show that these paradigms are inapt. Systems Biology does not quite converge with biology either: Although it certainly requires accurate 'stamp collecting', it discovers quantitative laws. Systems Biology is a science of its own, discovering own fundamental principles, some of which we identify here. Crown

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Implications of the Dominant Role of Transporters in Drug Uptake by Cells (Supplementary Material)

Cited by 84 publications

References 318 publications

Lead‐Oriented Synthesis: A New Opportunity for Synthetic Chemistry

Lead‐Oriented Synthesis: A New Opportunity for Synthetic Chemistry

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

Systems Biology: The elements and principles of Life

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