Competitive inhibition of HIV-1 protease by biphenyl carboxylic acids.
A novel series of nonpeptidic compounds that contain a biphenyl carboxylic acid group have been shown to inhibit HIV-1 protease. The active compounds, most of which are highly soluble, have IC50 values in the range of 3.4-74 microM. The structure-inhibitory activity relationship demonstrates the necessity of the biphenyl carboxylic acid group for inhibition, which is enhanced by the presence of a sulfone group and by halogenation of an adjacent phenyl group. A double reciprocal plot of inhibition data on two of the compounds clearly shows that the inhibition occurs in a competitive manner, with Ki values of 1.1 and 3.4 microM. Inhibition by several of the compounds was found to be reversible and fast-binding, while one of the biphenyl carboxylic acids inhibits in a reversible slow-binding manner. Time-dependent inhibition studies were conducted on this compound, and it was determined to have the kinetic values of kon = 0.18 microM-1min-1, koff = 9.7 x 10(-2)min-1, and Ki = 0.14 microM. Thus, the slow-binding inhibitor is the most potent in the series. Molecular modeling has provided information on a possible binding mode for two different biphenyl carboxylic acid inhibitors of HIV-1 protease.
Department of Biochemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105.
P J
PJ
Tummino
D
D
Ferguson
C M
CM
Jacobs
B
B
Tait
L
L
Hupe
E
E
Lunney
D
D
Hupe
D000595:Amino Acid Sequence; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology*; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000187:drug effects; D012995:Solubility
D001713:Biphenyl Compounds; D002264:Carboxylic Acids; D017320:HIV Protease Inhibitors; D011994:Recombinant Proteins