RESUMO
Small-molecule mimetics of the ß-hairpin flap of HIV-1 protease (HIV-1 PR) were designed based on a 1,4-benzodiazepine scaffold as a strategy to interfere with the flap-flap protein-protein interaction, which functions as a gated mechanism to control access to the active site. Michaelis-Menten kinetics suggested our small-molecules are competitive inhibitors, which indicates the mode of inhibition is through binding the active site or sterically blocking access to the active site and preventing flap closure, as designed. More generally, a new bioactive scaffold for HIV-1PR inhibition has been discovered, with the most potent compound inhibiting the protease with a modest K(i) of 11 µM.
Assuntos
Inibidores da Protease de HIV/síntese química , Protease de HIV/química , Bibliotecas de Moléculas Pequenas/química , Benzodiazepinas/química , Benzodiazepinas/metabolismo , Benzodiazepinas/farmacologia , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Protease de HIV/genética , Protease de HIV/metabolismo , Inibidores da Protease de HIV/metabolismo , Inibidores da Protease de HIV/farmacologia , HIV-1/enzimologia , HIV-1/fisiologia , Humanos , Concentração Inibidora 50 , Cinética , Ligação Proteica , Estrutura Secundária de Proteína , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
We herein report on the pharmacophore determination of the ERK docking domain inhibitor (Z)-3-(2-aminoethyl)-5-(4-ethoxybenzylidene)thiazolidine-2,4-dione, which has led to the discovery of compounds with greater selectivities for inhibiting the proliferation of melanoma cells containing active ERK signaling.
