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