RESUMEN
The goal of this study was to explore the applicability of surface plasmon resonance (SPR)-based fragment screening to identify compounds that bind to factor VIIa (FVIIa). Based on pharmacophore models virtual screening approaches, we selected fragments anticipated to have a reasonable chance of binding to the S1-binding pocket of FVIIa and immobilized these compounds on microarrays. In affinity fingerprinting experiments, a number of compounds were identified to be specifically interacting with FVIIa and shown to fall into four structural classes. The results demonstrate that the chemical microarray technology platform using SPR detection generates unique chemobiological information that is useful for de novo discovery and lead development and allows the detection of weak interactions with ligands of low molecular weight.
Asunto(s)
Diseño de Fármacos , Factor VIIa/antagonistas & inhibidores , Factor VIIa/metabolismo , Compuestos Orgánicos/química , Péptidos/química , Péptidos/síntesis química , Análisis por Matrices de Proteínas , Química Farmacéutica , Técnicas Químicas Combinatorias , Factor VIIa/química , Ligandos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Peso Molecular , Compuestos Orgánicos/síntesis química , Unión Proteica , Resonancia por Plasmón de SuperficieRESUMEN
Resin-bound 4H-1,3-oxazines are synthesized by the stepwise condensation of an amide resin, an aldehyde, and an alkyne. Upon DDQ activation, oxazines are converted into oxazinium salts. When treated with hydrazines, these resin-bound beta-diketone equivalents yield pyrazoles through a functionalizing release process. This multicomponent capture strategy, tedious to handle in classical synthesis in solution, is well-suited to solid-supported chemistry. It facilitates the handling of sensitive and unstable intermediates, such as N-alpha-methoxyalkylamides and 1,3-oxazinium salts.
