RESUMEN
Tropomyosin receptor kinases A (TrkA) is a potential therapeutic target for the treatment of numerous tumor types and chronic pain. However, most of the reported TrkA inhibitors are ATP competitive pan-Trks inhibitors that lack subtype selectivity. A selective TrkA inhibitor may provide valuable therapeutic benefits. Here, we described the discovery of novel TrkA allosteric inhibitors by structure-based virtual screening. A promising hit (D5261, TrkA cell IC50 = 3.32 µM) was selected for further studies. The binding free energy between TrkA and D5261 was calculated. In addition, the preliminary structure-activity relationship (SAR) studies with D5261 were investigated. The results suggest that D5261 can be used as a starting point for development of TrkA allosteric inhibitors.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Receptor trkA/antagonistas & inhibidores , Regulación Alostérica/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Receptor trkA/metabolismo , Relación Estructura-ActividadRESUMEN
Euscaphis japonica is not only an ideal ornamental plant, but also a traditional medicinal plant, which is an extremely valuable species to study. We determined the complete chloroplast genome sequence for E. japonica using Illumina sequencing technology. The complete chloroplast sequence is 160,467 bp in length, including a large single-copy (LSC) region of 88,716 bp, a small single-copy (SSC) region of 18,614 bp, and a pair of invert repeats (IR) regions of 26,568 bp. Plastid genome contains 142 genes, 46 protein-coding genes, 39 tRNA genes, and eight rRNA genes. Phylogenetic analysis base on 14 chloroplast genomes indicates that E. japonica forms an isolated clade and sisters to Glycosmis-Gossypium clade with strong support.