Structure-Based Dissection of the Natural Product Cyclopentapeptide Chitinase Inhibitor Argifin

Andersen, Ole A.; Nathubhai, Amit; Dixon, Mark J.; Eggleston, Ian M.; Aalten, Daan M. F. van

doi:10.1016/j.chembiol.2008.02.015

Cited by 59 publications

(74 citation statements)

References 40 publications

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“…Although Hajduk (8) did not show that the fragment positions are actually conserved, such data are available in a number of other studies. Andersen et al (9) shortened the natural cyclopentapeptide argifin, a chitinase inhibitor, to a series of dimethylguanyl-urea containing peptides and finally to dimethylguanyl-urea. The binding of fragments was analyzed by X-ray crystallography, and their conformations were shown to be similar to that observed in argifin.…”

mentioning

confidence: 99%

Ligand deconstruction: Why some fragment binding positions are conserved and others are not

Kozakov

Hall

Jehle

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

102

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Fragment-based drug discovery (FBDD) relies on the premise that the fragment binding mode will be conserved on subsequent expansion to a larger ligand. However, no general condition has been established to explain when fragment binding modes will be conserved. We show that a remarkably simple condition can be developed in terms of how fragments coincide with binding energy hot spots—regions of the protein where interactions with a ligand contribute substantial binding free energy—the locations of which can easily be determined computationally. Because a substantial fraction of the free energy of ligand binding comes from interacting with the residues in the energetically most important hot spot, a ligand moiety that sufficiently overlaps with this region will retain its location even when other parts of the ligand are removed. This hypothesis is supported by eight case studies. The condition helps identify whether a protein is suitable for FBDD, predicts the size of fragments required for screening, and determines whether a fragment hit can be extended into a higher affinity ligand. Our results show that ligand binding sites can usefully be thought of in terms of an anchor site, which is the top-ranked hot spot and dominates the free energy of binding, surrounded by a number of weaker satellite sites that confer improved affinity and selectivity for a particular ligand and that it is the intrinsic binding potential of the protein surface that determines whether it can serve as a robust binding site for a suitably optimized ligand.

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mentioning

confidence: 99%

Ligand deconstruction: Why some fragment binding positions are conserved and others are not

Kozakov

Hall

Jehle

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

102

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“…Although a simple arginine-derived inhibitor 2 discovered by van Aalten and co-workers had been reported independently, 13 it showed low inhibitory activity against SmChi in contrast to argifin 1, which was examined by our group (Figure 2). We synthesized the azide-bearing inhibitor 3 as a reactive scaffold for capturing complementary acetylenic reagents to form triazole-linked inhibitors by TGS.…”

Section: Resultsmentioning

confidence: 84%

“…In fact, van Aalten and co-workers revealed through X-ray analysis that the ability of the N o -methylcarbamoyl group to penetrate fully into the active-site pocket of chitinases strongly correlated with the inhibition of chitin hydrolysis. 13 Hence, we concluded that the N o -methylcarbamoyl-L-arginine core represents an ideal anchor to derivatize and elaborate better chitinase inhibitors.…”

Section: Introductionmentioning

confidence: 90%

Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry

et al. 2009

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In situ click chemistry is a target-guided synthesis technique for discovering potent protein ligands by assembling azides and alkynes into triazoles inside the affinity site of a target protein. We report the rapid discovery of a new and potent inhibitor of bacterial chitinases by the use of in situ click chemistry. We observed a target-templated formation of a potent triazole inhibitor of the chitinase-catalyzed chitin hydrolysis, through in situ click chemistry between a biologically active azide-containing scaffold and structurally unrelated alkyne fragments. Chitinase inhibitors have chemotherapeutic potential as fungicides, pesticides and antiasthmatics. Argifin, which has been isolated and characterized as a cyclopentapeptide natural product by our research group, shows strong inhibitory activity against chitinases. As a result of our efforts at developing a chitinase inhibitor from an azide-bearing argifin fragment and the application of the chitinase template and a library of alkynes, we rapidly obtained a very potent and new 1,5-disubstituted triazole inhibitor against Serratia marcescens chitinase (SmChi) B. The new inhibitor expressed 300-fold increase in the inhibitory activity against SmChiB compared with that of argifin. To the best of our knowledge, our finding of an enzyme-made 1,5-disubstituted triazole, using in situ click chemistry is the second example reported in the literature.

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“…For example, the large and counterintuitive enthalpic penalty associated with ligand binding to subsites +2 and +3 needs to be taken into account in current efforts to design chitinase inhibitors [31].…”

Section: Resultsmentioning

confidence: 99%

Determination of substrate binding energies in individual subsites of a family 18 chitinase

Norberg¹,

Karlsen²,

Hoell³

et al. 2010

FEBS Letters

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a b s t r a c tThermodynamic parameters for binding of N-acetylglucosamine (GlcNAc) oligomers to a family 18 chitinase, ChiB of Serratia marcescens, have been determined using isothermal titration calorimetry. Binding studies with oligomers of different lengths showed that binding to subsites À2 and +1 is driven by a favorable enthalpy change, while binding to the two other most important subsites, +2 and +3, is driven by entropy with unfavorable enthalpy. These remarkable unfavorable enthalpy changes are most likely due to favorable enzyme-substrate interactions being offset by unfavorable enthalpic effects of the conformational changes that accompany substrate-binding.

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Structure-Based Dissection of the Natural Product Cyclopentapeptide Chitinase Inhibitor Argifin

Cited by 59 publications

References 40 publications

Ligand deconstruction: Why some fragment binding positions are conserved and others are not

Ligand deconstruction: Why some fragment binding positions are conserved and others are not

Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry

Determination of substrate binding energies in individual subsites of a family 18 chitinase

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