Discovery and validation of novel drug combinations for pulmonary fibrosis via Traditional Chinese Medicine insights and computer screening.

BACKGROUND

Pulmonary fibrosis is a chronic interstitial lung disease that poses a serious threat to human health. The multi-target actions and favorable safety profile of Traditional Chinese Medicine (TCM) offer new therapeutic possibilities.

METHODS

We implemented an integrated strategy combining clinical expertise, computer-aided drug design (CADD), and TCM GuiJing theory for novel formula discovery. The interactions between TCM and disease targets were verified by molecular docking and molecular dynamics (MD) simulations. Furthermore, the efficacy of the newly discovered formulas was demonstrated by their correlation with ameliorated changes in the intestinal flora.

RESULTS

The core medicines used by famous doctors was Huangqi, and 69 groups of Huangqi-containing herb pairs were obtained. Using lung, heart, and spleen meridians as screening conditions, and by integrating the study of disease targets and compounds, the Huangqi-Gancao, Huangqi-Yinyanghuo, Huangqi-Ziwan, Huangqi-Tinglizi, and Huangqi-Mahuang pairs were identified as components of the potential new formula. All 95 molecular docking complexes exhibited favorable binding energies (ΔG ≤ -5.0 kcal/mol), and molecular dynamics stability was further determined. Moreover, these herbs may also be anti-pulmonary fibrosis by modulating the composition of gut microbiota, increasing Akkermansia abundance, and improving nicotinate and nicotinamide metabolism.

CONCLUSION

We establish an integrated TCM-GuiJing-CADD framework for the precision discovery of anti-fibrotic drug combinations. This strategy synthesizes clinical experience, CADD, and the GuiJing theory, providing a theoretical support for the precise application of TCM in treating complex diseases.