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Molecular modeling studies of "flap up" mannosyl cation mimics.

Abstract：

:The importance of inhibitors of glycosidases as therapeutic agents for viral, proliferative, and metabolic diseases is being increasingly recognised. Several years ago we reported that the activities of mannosidase inhibitors may be explained in terms of their similarity to the mannosyl cation intermediate postulated to form during the enzyme-catalyzed processing of oligosaccharide substrates. Recently, the validity of this model has been called in to question by some authors. We report recent molecular modeling studies undertaken to clarify this apparent contradiction. Mannostatin can indeed bind in a fashion which bears a close similarity to the mannosyl cation. Moreover we have shown that (-)-mannostatin is not able to adopt a similar binding mode to that of the mannosyl cation. As additional proof, Farr et al. have synthesized a trihydroxycyclopentylamine as a direct mimic of our mannosyl cation model. Satisfyingly, this compound shows potent inhibition of Jack Bean alpha-mannosidase, as predicted by the model. The inactivity of aminotrihydroxyhexahydro-1H-azepine against mannosidases can be explained in terms of the relative energies of the axial versus equatorial conformations of the critical hexahydroazepine ring substituents.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Winkler DA

doi

10.1021/jm960237z

subject

Has Abstract

pub_date

1996-10-11 00:00:00

pages

4332-4

issue

21

eissn

0022-2623

issn

1520-4804

pii

jm960237z

journal_volume

39

pub_type

杂志文章

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