New strategy of drug repositioning through anti‐fibrosis characteristic

Background Fibrosis is a common pathogenesis in most diseases, thus different diseases may share targets and drugs related to fibrosis. For a drug that targets fibrotic process, it is likely an effective drug for treating diseases other than its original purpose. Therefore, the current study aimed to investigate the anti‐fibrosis characteristic of drugs for repositioning purpose. Method Anti‐fibrosis compounds identified from PubMed and ClinicalTrials.gov were selected as positive samples. FDA‐approved drugs from DrugBank and compounds from Connectivity Map (CMap) were selected as potential negative samples after excluding those compounds known as anti‐fibrosis drugs. MACCS Keys fingerprint (RDKit) and molecule‐stimulated gene signatures (CMap) are collected as the structural descriptors and transcriptomic profiles of compounds respectively. OneClassSVM was used to remove outliers. Gradient Boosting Classifier was performed to build a Structural Model based on molecular structures and to build a Gene Model based on gene signatures to predict the anti‐fibrosis potentials of the compounds. Three external molecular sets: TCMID, ChEMBL and experimental drugs from DrugBank were used for model testing. Result 526 positive samples and 1248 negative samples were used to build the Structural Model that could predict the anti‐fibrosis potential of candidate compounds with an AUC value of 0.79. With the three molecule sets (TCMID, ChEMBL and DrugBank), 76.76%, 21.92% and 30.02% of the molecules, respectively, were identified as anti‐fibrosis molecules based on this Structural Model. As expected, most traditional chinese medicines with long history of clinical applications possess greater anti‐fibrosis potential that is consistent with their multi‐targeting effects. Among these candidates, 1‐peroxyferolide, peroxyparthenolide and formic acid are ranked to have higher success rates in drug repositioning. Similarly, the Gene Model was build with 851 positive samples and 1588 negative samples with an AUC value of 0.84. RPL30, PPIA and KLHL24 are identified as the preferred targets of drugs with anti‐fibrosis potential. Conclusion We first implemented a new strategy of drug repositioning through anti‐fibrosis characteristic, which may increase the success rate of novel applications of existing drugs. In addition traditional chinese medicines were found to have the highest anti‐fibrosis potentials and were considered the first choice in drugs repositioning for further studies. Support or Funding Information This work was supported by National Natural Science Foundation of China 81770571 (to LZ), 81774152(to RZ), 41530105 (to RZ). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .