Integrating Network Pharmacology, Molecular Dynamics, Machine Learning, and Animal Experiments to Decipher the Anti-fibrotic Mechanism of BI 1015550 in Idiopathic Pulmonary Fibrosis

Introduction: Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal lung disease with a poor prognosis. BI-1015550 is an oral phosphodiesterase 4B (PDE4B) inhibitor that has shown anti-inflammatory and anti-fibrotic effects; the exact molecular target(s) and mechanism of action in fibrosis are unknown. BI-1015550, an orally available PDE4B inhibitor with a possible anti-fibrotic effect, whose molecular mechanism of action is unknown Methods: We adopt an integrative approach that combines network pharmacology for identifying putative targets, molecular docking, and Molecular Dynamics (MD) simulations to assess the binding, ML-based target prioritization. Predicted targets/pathways were verified by Western blotting and Immunohistochemistry (IHC). Results: Network pharmacology analysis identified eight key targets: PTGS2, VCAM1, MMP1, IGF1, MMP7, CCL5, MMP13, and SELE. Docking results and MD simulation demonstrated that the predicted major targets of BI-1015550 include MMP1, PTGS2, and VCAM1. Therapeutic targets were also prioritized using machine learning methods. BI-1015550 treatment significantly decreased collagen deposition and HYP content of lung tissues in vivo. It down-regulated PTGS2, MMP1, and VCAM1 proteins via modulation of the NF-κB signaling pathway. Discussion: We presented an integrative multi-omics approach based on in silico prediction and wet-lab experiments to dissect the antifibrotic activity of BI-1015550. We showed here that BI- 1015550 mainly acts by inhibiting the NF-κB axis, resulting in downstream suppression of profibrotic and proinflammatory mediators. Our work on integrating network pharmacology with molecular simulation and ML is promising in both identifying reliable targets and providing a solid basis for further drug repurposing and mechanistic investigations. The better performance of BI-1015550 than current drugs (i.e., nintedanib and pirfenidone) demonstrates that it could be considered as an effective multi-target therapy against IPF. Conclusion: BI-1015550 attenuates idiopathic pulmonary fibrosis through the suppression of the NF-kB signalling pathway and up-regulation of PTGS2, MMP1, and VCAM1. This provides some theoretical basis to treat IPF with this compound and indicates that a combination study is beneficial for revealing drug mechanisms.