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Functional Chromatography Reveals Three Natural Products that Target the Same Protein with Distinct Mechanisms of Action
Author(s) -
Kang Min Jin,
Wu Tongde,
Wijeratne E. M. Kithsiri,
Lau Eric C.,
Mason Damian J.,
Mesa Celestina,
Tillotson Joseph,
Zhang Donna D.,
Gunatilaka A. A. Leslie,
La Clair James J.,
Chapman Eli
Publication year - 2014
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201402258
Subject(s) - natural product , small molecule , computational biology , drug discovery , affinity chromatography , recombinant dna , chemistry , chemical biology , biology , biochemistry , enzyme , gene
Access to lead compounds with defined molecular targets continues to be a barrier to the translation of natural product resources. As a solution, we developed a system that uses discrete, recombinant proteins as the vehicles for natural product isolation. Here, we describe the use of this functional chromatographic method to identify natural products that bind to the AAA+ chaperone, p97, a promising cancer target. Application of this method to a panel of fungal and plant extracts identified rheoemodin, 1‐hydroxydehydroherbarin, and phomapyrrolidone A as distinct p97 modulators. Excitingly, each of these molecules displayed a unique mechanism of p97 modulation. This discovery provides strong support for the application of functional chromatography to the discovery of protein modulators that would likely escape traditional high‐throughput or phenotypic screening platforms.