Design of potential anti-HIV agents. 1. Mannosidase inhibitors.
A molecular orbital and molecular graphics study of 12 substrates, inhibitors, reaction intermediates, and substrate analogues of alpha-mannosidase was undertaken. The results indicated that potent inhibitors must be good topographical analogues of the mannopyranosyl cation, an intermediate in the reaction catalyzed by the enzyme. Enzyme recognition and strong binding by the inhibitors requires that they contain, as part of their structure, electronegative atoms which are the topographical equivalent of the mannosyl cation C2 and C3 hydroxyl groups and ring heteroatom. The absence of a topographical analogue of the C4 hydroxyl group of the cation appeared to have little effect on the binding and activity of inhibitors. These results have been utilized in the design of potential anti-HIV drugs whose synthesis is now under consideration.
Winkler
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CSIRO Division of Chemicals and Polymers, Clayton, Australia.
Holan
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D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002412:Cations / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D015497:HIV-1 / Q000187:drug effects*; D037181:Lectins, C-Type; D008358:Mannose / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008361:Mannosidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic / Q000187:drug effects; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D017026:Swainsonine
D000470:Alkaloids; D000998:Antiviral Agents; D002412:Cations; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D008361:Mannosidases; D008358:Mannose; D017026:Swainsonine