Correction to "Discovering Proangiogenic Drugs in Ischemic Stroke Based on the Relationship between Protein Domain and Drug Substructure".

As an important protective mechanism against cerebral ischemia, angiogenesis has become a topic of interest in the treatment of ischemic stroke with the challenge that few drugs promote angiogenesis. Previous studies on the identification of drug-target interactions mainly focused on the overall structures of drugs and proteins, which limited the discovery of novel structure drugs. In this article, we proposed a new strategy to discover proangiogenic drugs based on the assumption that drug-protein interaction is mediated by substructure and domain. First, we identified substructure-domain relationships according to the known drug-protein interactions and established the drug-substructure-domain-protein relationships of genes which are proangiogenic in brain tissue and expressed significantly during ischemic stroke. Then we quantified the intensity of interaction between each drug and each protein. Finally, we obtained 540 interactive relationships between 238 drugs and 54 genes, establishing a drug-gene network with two patterns of independent and complex drug-gene interactions. Both of the patterns facilitated finding not only drugs with the same overall structure, but also drugs with the different overall structure based on the same or similar protein spectrum. In addition, we analyzed the mechanism of action of each predicted drug and extracted drugs with similar mechanisms. In vitro, our results showed that azelnidipine, azilsartan, lercanidipine, nafcillin and vortioxetine enhanced bEnd.3 cells proliferation, migration, tube formation and the expression of angiogenic marker PCNA. Azelnidipine, azilsartan, lercanidipine and nafcillin increased the expression of proangiogenic factor-VEGF. Unlike previous studies focusing on the overall structures of drugs, our research highlighted local structure similarity, which has great potential to discover more proangiogenic drugs with novel structures.