Identification and Characterization of Acidic Mammalian Chitinase Inhibitors

Cole, Derek C.; Olland, Andrea; Jacob, Jaison; Brooks, Jonathan; Bursavich, Matthew G.; Czerwiński, Robert; DeClercq, Charlene; Johnson, Matthew; Joseph‐McCarthy, Diane; Ellingboe, John W.; Lin, Laura; Nowak, Paweł; Presman, Ella; Strand, James; Tam, Amy; Williams, Cara; Yao, Shihua; Tsao, Désirée H.H.; Fitz, Lori

doi:10.1021/jm100533p

Cited by 41 publications

(37 citation statements)

References 41 publications

(73 reference statements)

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“…SPR biosensor assays are often used in fragment-based drug discovery as an orthogonal, complementary technique to confirm and validate the direct measurement of the kinetics and affinity of fragment hits discovered by other screening methods (Huber, 2005;Geschwindner et al, 2007;Godemann et al, 2009;Cole et al, 2010). However, in recent years SPR biosensor screening has become a primary screening method for fragment-based drug discovery (Giannetti, 2011), as it has several practical advantages over other techniques.…”

Section: Spr Fragment Screeningmentioning

confidence: 99%

Fragment screening by SPR and advanced application to GPCRs

Shepherd

Hopkins

Navrátilová

2014

Progress in Biophysics and Molecular Biology

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Surface plasmon resonance (SPR) is one of the primary biophysical methods for the screening of low molecular weight 'fragment' libraries, due to its low protein consumption and 'label-free' methodology. SPR biosensor interaction analysis is employed to both screen and confirm the binding of compounds in fragment screening experiments, as it provides accurate information on the affinity and kinetics of molecular interactions. The most advanced application of the use of SPR for fragment screening is against membrane protein drug targets, such G-protein coupled receptors (GPCRs). Biophysical GPCR assays using SPR have been validated with pharmacological measurements approximate to cell-based methods, yet provide the advantage of biophysical methods in their ability to measure the weak affinities of low molecular weight fragments. A number of SPR fragment screens against GPCRs have now been disclosed in the literature. SPR fragment screening is proving versatile to screen both thermostabilised GPCRs and solubilised wild type receptors. In this chapter, we discuss the state-of-the-art in GPCR fragment screening by SPR and the technical considerations in performing such experiments.

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Section: Spr Fragment Screeningmentioning

confidence: 99%

Fragment screening by SPR and advanced application to GPCRs

Shepherd

Hopkins

Navrátilová

2014

Progress in Biophysics and Molecular Biology

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“…1a,d), and these residues interact favorably with lipophilic molecules. Indeed, there has been growth in the number of medicinal chemistry-like glycoside hydrolase inhibitors identified using high-throughput screening of compound libraries [19][20][21] , fragment libraries 20 and 'virtual' in silico screening 20 . Initial hits from smaller academic libraries have generally yielded fair, but not exceptional, inhibitors having K i values generally in the micromolar range.…”

Section: Medicinal Chemistry-like Inhibitorsmentioning

confidence: 99%

“…Left, active site of TmGH1 in complex with glucoimidazole (PDB code 2CES). (d) Right, combination aglycon mimics: phenethyl-substituted glucoimidazole (20), PUGNAc (21) and N-hydroxyethyl deoxynojirimycin (miglitol; 3). Left value of inhibiting chitinase activity in humans 53 .…”

Section: Review Articlementioning

confidence: 99%

“…Indeed, both academics 55 and pharmaceutical companies have taken interest in AMCase. A striking example of glycoside hydrolase inhibitor development is the fragment-based and high-throughput screening approach that led to optimization of medicinal chemistry-based AMCase inhibitors such as 30 (K i = 210 nM) 20 . The bromobenzene group of 30 binds within a hydrophobic pocket inaccessible to allosamidin (Fig.…”

Section: Review Articlementioning

confidence: 99%

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Developing inhibitors of glycan processing enzymes as tools for enabling glycobiology

2012

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Glycoconjugates are ubiquitous biomolecules found in all kingdoms of life. These diverse structures are metabolically responsive and occur in a cell line- and protein-specific manner, conferring tissue type-specific properties. Glycans have essential roles in diverse processes, including, for example, intercellular signaling, inflammation, protein quality control, glucohomeostasis and cellular adhesion as well as cell differentiation and proliferation. Many mysteries remain in the field, however, and uncovering the physiological roles of various glycans remains a key pursuit. Realizing this aim necessitates the ability to subtly and selectively manipulate the series of different glycoconjugates both in cells and in vivo. Selective small-molecule inhibitors of glycan processing enzymes hold great potential for such manipulation as well as for determining the function of 'orphan' carbohydrate-processing enzymes. In this review, we discuss recent advances and existing inhibitors, the prospects for small-molecule inhibitors and the challenges associated with generating high-quality chemical probes for these families of enzymes. The coordinated efforts of chemists, biochemists and biologists will be crucial for creating and characterizing inhibitors that are useful tools both for advancing a basic understanding of glycobiology in mammals as well as for validating new potential therapeutic targets within this burgeoning field.

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“…24 Most of these compounds are natural products or their derivatives, and their use for either in vivo studies or as ligand design leads is significantly impeded by their limited availability and their chemical complexity and subsequent poor synthetic accessibility.…”

Section: à16mentioning

confidence: 99%

Bisdionin C—A Rationally Designed, Submicromolar Inhibitor of Family 18 Chitinases

Schüttelkopf

Andersen

Rao

et al. 2011

ACS Med. Chem. Lett.

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Chitinases of the GH18 family play important roles in a variety of pathogenic organisms and have also been shown to be involved in human asthma progression, making these enzymes potential drug targets. While a number of potent GH18 chitinase inhibitors have been described, in general, these compounds suffer from limited synthetic accessibility or unfavorable medicinal-chemical properties, making them poor starting points for the development of chitinase-targeted drugs. Exploiting available structural data, we have rationally designed bisdionin C, a submicromolar inhibitor of GH18 enzymes, that possesses desirable druglike properties and tractable chemical synthesis. A crystallographic structure of a chitinase-bisdionin C complex shows the two aromatic systems of the ligand interacting with two conserved tryptophan residues exposed in the active site cleft of the enzyme, while at the same time forming extensive hydrogen-bonding interactions with the catalytic machinery. The observed mode of binding, together with inhibition data, suggests that bisdionin C presents an attractive starting point for the development of specific inhibitors of bacterial-type, but not plant-type, GH 18 chitinases.

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Identification and Characterization of Acidic Mammalian Chitinase Inhibitors

Cited by 41 publications

References 41 publications

Fragment screening by SPR and advanced application to GPCRs

Fragment screening by SPR and advanced application to GPCRs

Developing inhibitors of glycan processing enzymes as tools for enabling glycobiology

Bisdionin C—A Rationally Designed, Submicromolar Inhibitor of Family 18 Chitinases

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