Integrated ML-Based Strategy Identifies Drug Repurposing for Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) affects an estimated
global
population of around 3 million individuals. IPF is a medical condition
with an unknown cause characterized by the formation of scar tissue
in the lungs, leading to progressive respiratory disease. Currently,
there are only two FDA-approved small molecule drugs specifically
for the treatment of IPF and this has created a demand for the rapid
development of drugs for IPF treatment. Moreover, denovo drug development
is time and cost-intensive with less than a 10% success rate. Drug
repurposing currently is the most feasible option for rapidly making
the drugs to market for a rare and sporadic disease. Normally, the
repurposing of drugs begins with a screening of FDA-approved drugs
using computational tools, which results in a low hit rate. Here,
an integrated machine learning-based drug repurposing strategy is
developed to significantly reduce the false positive outcomes by introducing
the predock machine-learning-based predictions followed by literature
and GSEA-assisted validation and drug pathway prediction. The developed
strategy is deployed to 1480 FDA-approved drugs and to drugs currently
in a clinical trial for IPF to screen them against “TGFB1”,
“TGFB2”, “PDGFR-a”, “SMAD-2/3”,
“FGF-2”, and more proteins resulting in 247 total and
27 potentially repurposable drugs. The literature and GSEA validation
suggested that 72 of 247 (29.14%) drugs have been tried for IPF, 13
of 247 (5.2%) drugs have already been used for lung fibrosis, and
20 of 247 (8%) drugs have been tested for other fibrotic conditions
such as cystic fibrosis and renal fibrosis. Pathway prediction of
the remaining 142 drugs was carried out resulting in 118 distinct
pathways. Furthermore, the analysis revealed that 29 of 118 pathways
were directly or indirectly involved in IPF and 11 of 29 pathways
were directly involved. Moreover, 15 potential drug combinations are
suggested for showing a strong synergistic effect in IPF. The drug
repurposing strategy reported here will be useful for rapidly developing
drugs for treating IPF and other related conditions.