Inhibition of Golgi mannosidase II with mannostatin A analogues: synthesis, biological evaluation, and structure-activity relationship studies.

Article Details

Citation

Copy to clipboard

Li B, Kawatkar SP, George S, Strachan H, Woods RJ, Siriwardena A, Moremen KW, Boons GJ

Inhibition of Golgi mannosidase II with mannostatin A analogues: synthesis, biological evaluation, and structure-activity relationship studies.

Chembiochem. 2004 Sep 6;5(9):1220-7.

PubMed ID

15368573 [ View in PubMed

]

Abstract

Mannostatin and aminocyclopentitetrol analogues with various substitutions at the amino function were synthesized. These compounds were tested as inhibitors of human Golgi and lysosomal alpha-mannosidases. Modification of the amine of mannostatin had only marginal effects, whereas similar modifications of aminocyclopentitetrol led to significantly improved inhibitors. Ab initio calculations and molecular docking studies were employed to rationalize the results. It was found that mannostatin and aminocyclopentitretrol could bind to Golgi alpha-mannosidase II in a similar mode to that of the known inhibitor swainsonine. However, due to the flexibility of the five-membered rings of these compounds, additional low-energy binding modes could be adopted. These binding modes may be relevant for the improved activities of the benzyl-substituted compounds. The thiomethyl moiety of mannostatin was predicted to make favorable hydrophobic interactions with Arg228 and Tyr727 that would possibly account for its greater inhibitory activity.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(1R,2R,3R,4S,5R)-4-(Benzylamino)-5-(methylthio)cyclopentane-1,2,3-triol	Alpha-mannosidase 2	Ki (nM)	8.80E+02	5.6	37	Details
(1R,2R,3R,4S,5R)-4-(Benzylamino)-5-(methylthio)cyclopentane-1,2,3-triol	Alpha-mannosidase 2	Ki (nM)	1.10E+02	5.6	37	Details