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PubMed · 12469352

A case study in conformation design: learning by doing.

Henner Knust·Reinhard W Hoffmann
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Abstract

Efforts are described to design simple, fully flexible but conformationally preorganised omega-hydroxy-nonanoic acids that could serve as the conformation controlling unit in analogues of the potent protein-kinase C activator aplysiatoxin. Such analogues are macrodilactones incorporating the designed omega-hydroxy-nonanoic acid and 3,4-dihydroxy-pentanoic acid, which contains the pharmacophoric groups. The design process (replacement of CH(2) groups by an oxygen atom, annelation of a six-membered ring and placement of alkyl substituents) of the omega-hydroxy-nonanoic acids was monitored by force-field calculations. In the end of this process simple analogues of aplysiatoxin are proposed in which the proper disposition of the pharmacophoric groups is secured by a conformationally flexible but preorganised template structure as part of the macrodilactone ring.

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Drug DesignLearningLyngbya ToxinsModels, MolecularMolecular ConformationJournal ArticleResearch Support, Non-U.S. Gov't

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Henner Knust, Reinhard W Hoffmann. 2002. A case study in conformation design: learning by doing.. https://doi.org/10.1002/tcr.10038

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