Use of in-silico assays to characterize the ADMET profile and identify potential therapeutic targets of fusarochromanone, a novel anti-cancer agent

摘要: For 30 years nature has provided a plethora of natural products with potential meaningful anti-cancer activity. Fusarochromanone (FC101a) is small molecule fungal metabolite exhibiting potent in-vitro growth inhibitory effects and capable inducing apoptosis, suppressing angiogenesis tumorigenesis, inhibiting endothelial cell in multiple cancer lines. Despite all we know regarding FC101a, the mechanism action molecular target(s) this compound have remained an enigma. Furthermore, modest in-vivo activity been documented requires addressing. Early stage pharmacokinetics (PK) assessment vital to successful drug development. Herein, aimed use in-silico assays i) characterize in-depth ADMET profile FC101a ii) probe for possible therapeutic targets. Two-dimensional SDF files 13 analogs were introduced into Predictor Version 7.1 that parses structures order calculate descriptors, which are used estimate properties. Calculated values analyzed subjected drug-like indices, delivering PK each analog. To targets, total 49 proteins SYBYL-X 2.0 platform deepest binding pocket protein was virtually docked parent compound, FC101a; negative control, FC101b; model kynurenine. Each analog showed promising qualities, although FC101 Oxazole identified as most optimized having desirable ADME toxicity profile, areas concern must be addressed in-vitro. These include mutagenic properties estrogen receptor toxicity. We provide avenues medicinal chemists could achieve higher effective permeation, blood brain barrier (BBB) penetration, aqueous solubility FC101a. Molecular docking revealed procaspase-8 - cFLIP(L) complex biological target led proposed mechanisms by facilitates heterodimerization, thereby increasing proteolytic up regulating extrinsic apoptosis. Our data both attributes render lead candidate development low toxic agent against broad range cancers.