Inverse in silico-in vitro fishing of unexpected paroxetine kinase targets from tumor druggable kinome.

摘要: The serotonin selective reuptake inhibitor paroxetine has been clinically observed to reposition a significant suppressing potency on human tumors by unexpectedly targeting diverse kinase pathways involved in tumorigenesis. Here, we describe an inverse silico–in vitro strategy fish potential targets using the as bait. This is different (inverse) traditional drug discovery process that commonly screens small-molecule inhibitors for specific target. In procedure, cell viability assays demonstrate strong cytotoxicity tumor lines. Various protooncogene protein kinases are ontologically/manually enriched define druggable kinome, and systematic interaction profile of with kinome created, which indicates can potentially bind some known or key regulators tumors. Kinase determine effectively inhibit c-Src family at nanomolar micromolar levels. It ligand forms tightly packed interface against active site these unexpected constitute several hydrogen bonds/π–π/cation–π stackings number nonspecific hydrophobic/vdW contacts, while exposing portion molecular surface solvent. More significantly, adopts two distinct binding modes (i.e., class I II) interact kinases; class-I mode higher stability inhibitory activity than class-II mode. Steric clash seems cause flipping from II.