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Affinity crystallography: a new approach to extracting high-affinity enzyme inhibitors from natural extracts

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dc.contributor.authorAguda, Adeleke H.
dc.contributor.authorLavallee, Vincent
dc.contributor.authorCheng, Ping
dc.contributor.authorBott, Tina
dc.contributor.authorMeimetis, Labros G.
dc.contributor.authorLaw, Simon
dc.contributor.authorNguyen, Nham T.
dc.contributor.authorWilliams, David E.
dc.contributor.authorKaleta, Jadwiga
dc.contributor.authorVillanueva, Ivan
dc.contributor.authorDavies, Julian
dc.contributor.authorAndersen, Raymond J.
dc.contributor.authorBrayer, Gary D.
dc.contributor.authorBrömme, Dieter
dc.date.accessioned2021-05-18
dc.date.accessioned2022-05-31T01:43:38Z
dc.date.available2022-05-31T01:43:38Z
dc.date.issued2016
dc.description.abstractNatural products are an important source of novel drug scaffolds. The highly variable and unpredictable timelines associated with isolating novel compounds and elucidating their structures have led to the demise of exploring natural product extract libraries in drug discovery programs. Here we introduce affinity crystallography as a new methodology that significantly shortens the time of the hit to active structure cycle in bioactive natural product discovery research. This affinity crystallography approach is illustrated by using semipure fractions of an actinomycetes culture extract to isolate and identify a cathepsin K inhibitor and to compare the outcome with the traditional assay-guided purification/structural analysis approach. The traditional approach resulted in the identification of the known inhibitor antipain (1) and its new but lower potency dehydration product 2, while the affinity crystallography approach led to the identification of a new high-affinity inhibitor named lichostatinal (3). The structure and potency of lichostatinal (3) was verified by total synthesis and kinetic characterization. To the best of our knowledge, this is the first example of isolating and characterizing a potent enzyme inhibitor from a partially purified crude natural product extract using a protein crystallographic approach.
dc.description.urihttps://library.macewan.ca/cgi-bin/SFX/url.pl/BYG
dc.identifier.citationAguda, A. H., Lavallee, V., Cheng, P., Bott, T. M., Meimetis, L. G., Law, S., Nguyen, N. T., Williams, D. E.; Kaleta, J., Villanueva, I., Davies, J., Andersen, R. J., Brayer, G. D., and Brömme, D. (2016). Affinity crystallography: A new approach to extracting high-affinity enzyme inhibitors from natural extracts. Journal of Natural Products, 79(8), 1962–1970. https://doi.org/10.1021/acs.jnatprod.6b00215
dc.identifier.doihttps://doi.org/10.1021/acs.jnatprod.6b00215
dc.identifier.urihttps://hdl.handle.net/20.500.14078/2278
dc.languageEnglish
dc.language.isoen
dc.rightsAll Rights Reserved
dc.subjectmixtures
dc.subjectcrystallography
dc.subjectinhibitors
dc.subjectpeptides and proteins
dc.subjectpharmaceuticals
dc.titleAffinity crystallography: a new approach to extracting high-affinity enzyme inhibitors from natural extractsen
dc.typeArticle

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Department of Physical Sciences