RESUMEN
Efforts directed to identifying potent HIV protease inhibitors (PI) have yielded a class of compounds that are not only very active against wild-type (NL4-3) HIV virus but also very potent against a panel of PI-resistant viral isolates. Chemistry and biology are described.
Asunto(s)
Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , VIH/efectos de los fármacos , Indinavir/análogos & derivados , Administración Oral , Disponibilidad Biológica , Farmacorresistencia Viral , VIH/enzimología , Proteasa del VIH/efectos de los fármacos , Inhibidores de la Proteasa del VIH/administración & dosificación , Estructura MolecularRESUMEN
Molecular modeling has been used to assist in the development of a novel series of potent glycogen phosphorylase inhibitors based on a phenyl diacid lead, compound 1. In the absence of suitable competitive binding assays, compound 1 was predicted to bind at the AMP allosteric site based on superposition onto known inhibitors which bind at different sites in the enzyme and analyses of the surrounding protein environment associated with these distinct sites. Possible docking modes of compound 1 at the AMP allosteric site were further explored using the crystal structure of rabbit muscle glycogen phosphorylase complexed with a Bayer diacid compound W1807 (PDB entry 3AMV). Compound 1 was predicted to interact with positively charged arginines at the AMP allosteric site in the docking model. Characterization of the binding pocket by a grid-based surface calculation of the docking model revealed a large unfilled hydrophobic region near the central phenyl ring, suggesting that compounds with larger hydrophobic groups in this region would improve binding. A series of naphthyl diacid compounds were designed and synthesized to access this hydrophobic cleft, and showed significantly improved potency.
Asunto(s)
Diseño Asistido por Computadora , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glucógeno Fosforilasa/antagonistas & inhibidores , Adenosina Monofosfato/metabolismo , Sitio Alostérico , Glucógeno Fosforilasa/química , Glucógeno Fosforilasa/metabolismo , Glucógeno Fosforilasa de Forma Hepática/antagonistas & inhibidores , Glucógeno Fosforilasa de Forma Hepática/química , Glucógeno Fosforilasa de Forma Hepática/metabolismo , Glucógeno Fosforilasa de Forma Muscular/antagonistas & inhibidores , Glucógeno Fosforilasa de Forma Muscular/química , Glucógeno Fosforilasa de Forma Muscular/metabolismo , Humanos , Técnicas In Vitro , Plomo/química , Plomo/farmacología , Modelos Químicos , Estructura Molecular , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , TermodinámicaRESUMEN
A new class of diacid analogues that binds at the AMP site not only are very potent but have approximately 10-fold selectivity in liver versus muscle glycogen phosphorylase (GP) in the in vitro assay. The synthesis, structure, and in vitro and in vivo biological evaluation of these liver selective glycogen phosphorylase inhibitors are discussed.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Glucógeno Fosforilasa/antagonistas & inhibidores , Naftoles/síntesis química , Adenosina Trifosfato/metabolismo , Secuencia de Aminoácidos , Animales , Sitios de Unión , Glucógeno Fosforilasa/química , Cinética , Hígado/enzimología , Ratones , Modelos Moleculares , Conformación Molecular , Naftoles/farmacología , Conformación Proteica , Ratas , Relación Estructura-ActividadRESUMEN
A series of highly potent HIV protease inhibitors have been designed and synthesized. These compounds are active against various clinical viral isolates as well as wild-type virus. The synthesis and biological activity of these HIV protease inhibitors are discussed.
