Document 0436
 DOCN  M9490436
 TI    Crystal-structure-based design and synthesis of novel C-terminal
       inhibitors of HIV protease.
 DT    9411
 AU    Varney MD; Appelt K; Kalish V; Reddy MR; Tatlock J; Palmer CL; Romines
       WH; Wu BW; Musick L; Agouron Pharmaceuticals, Inc., San Diego,
       California 92121.
 SO    J Med Chem. 1994 Jul 22;37(15):2274-84. Unique Identifier : AIDSLINE
       MED/94334881
 AB    The X-ray crystal-structure-based design, synthesis, computational
       evaluation, and activity of a novel class of HIV protease inhibitors are
       described. The initial lead compounds 2 and 3 were designed by modeling
       replacement groups for the C-terminal Val-Val-OCH3 of a known
       hydroxyethylene inhibitor into the active site of the reported crystal
       structure of HIV protease complexed with MVT-101. The lead compound 2
       was found to be a modest inhibitor with a Ki = 1.67 microM. The X-ray
       crystal structure of compound 2 complexed with HIV protease was solved
       and used for subsequent design. The lead compound 3 was found to be a
       more potent inhibitor with Ki = 0.2 microM, and the structure of it
       complexed with HIV protease was also solved and used for subsequent
       design. Modification of both the C-terminus and N-terminus of indole 3
       resulted in compounds with Ki = 30 nM. Using the crystal structure of
       compounds 2 and 3 with HIV protease as a starting point, the
       thermodynamic cycle perturbation molecular dynamics method was applied
       to a select group of compounds in order to test the accuracy of this
       type of computation within a series of closely related compounds.
 DE    Crystallography, X-Ray  *Drug Design  HIV Protease Inhibitors/*CHEMISTRY
       Thermodynamics  JOURNAL ARTICLE

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