De novo design of nonpeptidic HIV-1 protease inhibitors: Incorporation of structural water

We describe the de novo structure-based design of C 2 symmetric, non-peptidic HIV PR inhibitors. Cyclic ureas were chosen as synthetic targets owing to their ability to mimic key interacting elements observed in known HIV PR/inhibitor complexes. The urea carbonyl oxygen serves as a replacement for t...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 1994-05, Vol.4 (10), p.1247-1252
Main Authors: Randad, Ramnarayan S., Pan, Wenxi, Gulnik, Sergei V., Burt, Stanley, Erickson, John W.
Format: Article
Language:English
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Summary:We describe the de novo structure-based design of C 2 symmetric, non-peptidic HIV PR inhibitors. Cyclic ureas were chosen as synthetic targets owing to their ability to mimic key interacting elements observed in known HIV PR/inhibitor complexes. The urea carbonyl oxygen serves as a replacement for the buried, structural water that occurs in peptide-based inhibitor complexes. The conformational analysis of the six-membered pyrimidone ring suggests that N-substituted derivatives should exhibit a marked stereochemical preference for binding.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(01)80339-5