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3 Challenges in Screening
Pages 13-18

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From page 13...
... Off-target toxicity is often the real source natural product libraries, she said. To illustrate the failure of antimicrobial activity, even with compounds generated of both approaches, she recounted the results of a seven- in chemical optimization programs.
From page 14...
... "What matters is having a molecule in prioritize potential hits for further study. For nucleic acid hand, even if it's a weak hit, and a target that it binds to," hits, subsequent screens looking at specific mechanisms of Shaw explained, since that then gives medicinal chemists a action, such as inhibitors of DNA polymerase or ligase, and molecule that they can try to optimize to improve its bacte- at general nucleic acid binding or DNA intercalation were rial toxicity.
From page 15...
... The challenge with this approach, which is samples and fractions from marine sources, Shaw said that being pursued by a company called Siernas, is data analysis, about seven percent demonstrated antimicrobial activity. but it is being used to identify novel compounds that then Macromolecular synthesis inhibition eliminated 80 percent can be put through antibacterial screens.
From page 16...
... of that have a chance of reviving the discovery of new natu- When the TTSS was first characterized, medicinal chemists ral antibacterial natural products," said Chaitan Khosla. The screened large numbers of existing medicinal chemistry first, highlighted in the presentations by Silver and Shaw, libraries with little success until the discovery in 2008 by is the tried and true method of conventional activity-based a group in Japan of a new type of antibiotic that "doesn't screening, though today driven by new methodologies.
From page 17...
... research groups, including his, are developing promising Khosla noted during the discussion period that some of methods of expressing the very large proteins that make these the products of the polyketide assembly lines are further assembly lines, another challenge facing the field, but more modified by oxidases, oxygenases, and transferases. In work is needed to identify methods of tailoring enzymes to most cases, the biochemistry and genomic locations of these create novel structures and to address the supply of all but adjunct "tailoring" enzymes have been described in the the simplest precursor molecules to feed into these assem- literature.
From page 18...
... 2006. Discovery of FabH/FabF inhibitors from natural products.


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