Screening study of antifibrotic drug targeting platelet derived growth factor-BB
Objective Platelet derived growth factor-BB (PDGF-BB) plays a crucial role in the occurrence and development of liver fibrosis. Surface plasmon resonance (SPR) technology was utilized to identify potential drugs that directly target PDGF-BB,providing a foundation for the development of antifibrotic drugs.Methods Using the molecular interaction detection system based on SPR technology,a high-throughput SPR screening method was established by utilizing the human recombinant PDGF-BB protein with histidine tag (His-tag). A total of 1760 FDA-approved drugs and 640 natural products were screened and compounds capable of binding to PDGF-BB were preliminarily obtained. Further biological verification of the anti-fibrotic effect of the screened compounds was further investigated in human hepatic stellate cells (LX-2 cells) activated by PDGF-BB. Finally,the molecular docking technology was utilized to predict the possible binding sites and patterns of the compounds with PDGF-BB.Results We established a well SPR high-throughput screening model targeting PDGF-BB and lomefloxacin,acefylline,lovastatin,salvianolic acid C,pilocarpine nitrate,and dabigatran etexilate were found to bind directly to PDGF-BB. In vitro results confirmed that the above six compounds reduced the mRNA level of fibrosis marker gene COL1A1 in the LX-2 cells activated by PDGF-BB,and among them lomefloxacin was verified to significantly reduce the fibrosis factor COL1A1 and α-SMA (ACTA2) and PDGF-BB receptor PDGFRβ at mRNA and protein levels. Molecular docking results indicated that lomefloxacin formed hydrogen bound with Asn34 of PDGF-BB protein to promote the formation of a complex.Conclusions We establish a SPR high-throughput screening model targeting PDGF-BB and discover,for the first time,that lomefloxacin may serve as a potential antifibrotic drug that directly targets PDGF-BB allowing for the development of new application of lomefloxacin.
万方数据
维普
