Document 2281
 DOCN  M94A2281
 TI    Structures of cyclic ureas complexed with native and V821 mutant HIV-1
       protease.
 DT    9412
 AU    Chang CH; DeLoskey RL; Lam P; Schadt M; Duke J; Weber PC; DuPont Merck
       Pharmaceutical Co., Wilmington, DE.
 SO    Int Conf AIDS. 1994 Aug 7-12;10(1):34 (abstract no. 110A). Unique
       Identifier : AIDSLINE ICA10/94370294
 AB    OBJECTIVE: To utilize the structural information of the inhibitor
       binding mode both in native and mutant HIV proteases for the design of
       an improved drug. METHODS: The structures of HIV PR complexed with the
       molecule below have been determined to 1.8 A. Complexes crystallize in a
       hexagonal space group P6(1) (a = b = 62.8A, c = 83.5 A).
       Crystallographic refinement by simulated annealing resulted in a final
       R-factor in the low 20's. RESULTS: In all 4 structures, the 7-membered
       ring binds in a similar fashion. The carbonyl oxygen atom of cyclic urea
       replaces the structural water molecule found in many complexes of linear
       peptidomimetic inhibitors (Lam et al., Science, 263, 380-384, 1994). The
       P1 and P2 groups of the cyclic urea occupy the same pockets as reported
       for the linear inhibitors. However, the hydroxyl groups attached to the
       ring make different interactions with the catalytic aspartates than
       those of the linear inhibitors. These and other differences among the
       three structures and that of native and mutant structures will be
       discussed in detail. DISCUSSION AND CONCLUSION: These novel nonpeptide
       cyclic urea show high affinity and specificity for the enzyme. This is
       an excellent example of structure-based drug design, and some of these
       compounds are potent, safe, inhibitors of the HIV protease. TABULAR
       DATA, SEE ABSTRACT VOLUME.
 DE    *Drug Design  *HIV Protease/GENETICS  Molecular Structure  Mutation  R
       Factors  *Urea  MEETING ABSTRACT

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).