Discovery of pulmonary fibrosis inhibitor targeting TGF-β RI in Polygonum cuspidatum by high resolution mass spectrometry with in silico strategy / 药物分析学报

ABSTRACT

Pulmonary fibrosis(PF)is an irreversible lung disease that is characterized by excessive scar tissue with a poor median survival rate of 2-3 years.The inhibition of transforming growth factor-β receptor type-Ⅰ(TGF-β RI)by an appropriate drug may provide a promising strategy for the treatment of this disease.Polygonum cuspidatum(PC)is a well-known traditional Chinese herbal medicine which has an anti-PF effect.Accordingly,a combination of high resolution mass spectrometry with an in silico strategy was developed as a new method to search for potential chemical ingredients of PC that target the TGF-β RI.Based on this strategy,a total of 24 ingredients were identified.Then,absorption,distribution,meta-bolism,and excretion(ADME)-related properties were subsequently predicted to exclude compounds with potentially undesirable pharmacokinetics behaviour.Molecular docking studies on TGF-β RI were adopted to discover new PF inhibitors.Eventually,a compound that exists in PC known as resveratrol was proven to have excellent biological activity on TGF-β RI,with an ICso of 2.211 μM in vitro.Furthermore,the complex formed through molecular docking was tested via molecular dynamics simulations,which revealed that resveratrol had strong interactions with residues of TGF-β RI.This study revealed that resveratrol has significant potential as a treatment for PF due to its ability to target TGF-β RI.In addition,this research demonstrated the exploration of natural products with excellent biological activities toward specific targets via high resolution mass spectrometry in combination with in silico technology is a promising strategy for the discovery of novel drugs.