Crystal-structure-based design and synthesis of novel C-terminal inhibitors of HIV protease.
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.
Varney
M D
MD
Agouron Pharmaceuticals, Inc., San Diego, California 92121.
Appelt
K
K
Kalish
V
V
Reddy
M R
MR
Tatlock
J
J
Palmer
C L
CL
Romines
W H
WH
Wu
B W
BW
Musick
L
L
D018360:Crystallography, X-Ray; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D013816:Thermodynamics
D017320:HIV Protease Inhibitors