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In situ extension as an approach for identifying novel alpha-amylase inhibitors.

Numao S, Damager I, Li C, Wrodnigg TM, Begum A, Overall CM, Brayer GD, Withers SG
J Biol Chem 279 48282-91 (2004)
Related entries: 1u2y, 1u33

Cited: 7 times
EuropePMC logo PMID: 15304511

Abstract

A new approach for the discovery and subsequent structural elucidation of oligosaccharide-based inhibitors of alpha-amylases based upon autoglucosylation of known alpha-glucosidase inhibitors is presented. This concept, highly analogous to what is hypothesized to occur with acarbose, is demonstrated with the known alpha-glucosidase inhibitor, d-gluconohydroximino-1,5-lactam. This was transformed from an inhibitor of human pancreatic alpha-amylase with a K(i) value of 18 mm to a trisaccharide analogue with a K(i) value of 25 mum. The three-dimensional structure of this complex was determined by x-ray crystallography and represents the first such structure determined with this class of inhibitors in any alpha-glycosidase. This approach to the discovery and structural analysis of amylase inhibitors should be generally applicable to other endoglucosidases and readily adaptable to a high throughput format.

Reviews citing this publication (3)

  1. Analysis of carbohydrates and glycoconjugates by matrix-assisted laser desorption/ionization mass spectrometry: An update for 2003-2004. Harvey DJ. Mass Spectrom Rev 28 273-361 (2009)
  2. First principles insight into the alpha-glucan structures of starch: their synthesis, conformation, and hydration. Damager I, Engelsen SB, Blennow A, Møller BL, Motawia MS. Chem Rev 110 2049-2080 (2010)
  3. Empirical Scoring Functions for Structure-Based Virtual Screening: Applications, Critical Aspects, and Challenges. Guedes IA, Pereira FSS, Dardenne LE. 9 1089 (2018)

Articles citing this publication (4)

  1. Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock. Bikadi Z, Hazai E. 1 15 (2009)
  2. The search for novel human pancreatic alpha-amylase inhibitors: high-throughput screening of terrestrial and marine natural product extracts. Tarling CA, Woods K, Zhang R, Brastianos HC, Brayer GD, Andersen RJ, Withers SG. Chembiochem 9 433-438 (2008)
  3. Development of an active site titration reagent for α-amylases. Sweeney RP, Danby PM, Geissner A, Karimi R, Brask J, Withers SG. Chem Sci 12 683-687 (2020)
  4. Synthesis of montbretin A analogues yields potent competitive inhibitors of human pancreatic α-amylase. Tysoe CR, Caner S, Calvert MB, Win-Mason A, Brayer GD, Withers SG. Chem Sci 10 11073-11077 (2019)


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