RESUMEN
Macrophage migration inhibitory factor (MIF) is an upstream regulator of the immune response whose dysregulation is tied to a broad spectrum of inflammatory and proliferative disorders. As its complex signaling pathways and pleiotropic nature have been elucidated, it has become an attractive target for drug discovery. Remarkably, MIF is both a cytokine and an enzyme that functions as a keto-enol tautomerase. Strategies including in silico modeling, virtual screening, high-throughput screening, and screening of anti-inflammatory natural products have led to a large and diverse catalogue of MIF inhibitors as well as some understanding of the structure-activity relationships for compounds binding MIF's tautomerase active site. With possible clinical trials of some MIF inhibitors on the horizon, it is an opportune time to review the literature to seek trends, address inconsistencies, and identify promising new avenues of research.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Inflamación/tratamiento farmacológico , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Factores Inhibidores de la Migración de Macrófagos/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Descubrimiento de Drogas , Humanos , Relación Estructura-ActividadRESUMEN
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is implicated in the regulation of inflammation, cell proliferation, and neurological disorders. MIF is also an enzyme that functions as a keto-enol tautomerase. Most potent MIF tautomerase inhibitors incorporate a phenol, which hydrogen bonds to Asn97 in the active site. Starting from a 113-µm docking hit, we report results of structure-based and computer-aided design that have provided substituted pyrazoles as phenol alternatives with potencies of 60-70â nm. Crystal structures of complexes of MIF with the pyrazoles highlight the contributions of hydrogen bonding with Lys32 and Asn97, and aryl-aryl interactions with Tyr36, Tyr95, and Phe113 to the binding.