Background The traditional Chinese medicine (TCM) formula Qing-Fei-Pai-Du decoction (QFPDD) was the most widely used prescription in China's campaign to contain COVID-19, which has exhibited positive effects. However, the underlying mode of action is largely unknown. Purpose A systems pharmacology strategy was proposed to investigate the mechanisms of QFPDD against COVID-19 from molecule, pathway and network levels. Study design and methods The systems pharmacological approach consisted of text mining, target prediction, data integration, network study, bioinformatics analysis, molecular docking, and pharmacological validation. Especially, we proposed a scoring method to measure the confidence of targets identified by prediction and text mining, while a novel scheme was used to identify important targets from 4 aspects. Results 623 high-confidence targets of QFPDD's 12 active compounds were identified, 88 of which were overlapped with genes affected by SARS-CoV-2 infection. These targets were found to be involved in biological processes related with the development of COVID-19, such as pattern recognition receptor signaling, interleukin signaling, cell growth and death, hemostasis, and injuries of the nervous, sensory, circulatory, and digestive systems. Comprehensive network and pathway analysis were used to identify 55 important targets, which regulated 5 functional modules corresponding to QFPDD's effects in immune regulation, anti-infection, anti-inflammation, and multi-organ protection, respectively. Four compounds (baicalin, glycyrrhizic acid, hesperidin, and hyperoside) and 7 targets (AKT1, TNF-α, IL6, PTGS2, HMOX1, IL10, and TP53) were key molecules related to QFPDD's effects. Molecular docking verified that QFPDD's compounds may bind to 6 host proteins that interact with SARS-CoV-2 proteins, further supported the anti-virus effect of QFPDD. At last, in intro experiments validated QFPDD's important effects, including the inhibition of IL6, CCL2, TNF-α, NF-κB, PTGS1/2, CYP1A1, CYP3A4 activity, the up-regulation of IL10 expression, and repressing platelet aggregation. Conclusion This work illustrated that QFPDD could exhibit immune regulation, anti-infection, anti-inflammation, and multi-organ protection. It may strengthen the understanding of QFPDD and facilitate more application of this formula in the campaign to SARS-CoV-2.

Methylophiopogonanone A (MOA), an abundant homoisoflavonoid bearing a methylenedioxyphenyl (MDP) moiety, is one of the major consitituents in the Chinese herb Ophiopogon japonicas. This work aims to assess the inhibitory potentials of MOA against cytochrome P450 enzymes, as well as to decipher the molecular mechanisms for CYP inhibition by MOA. The results showed that MOA concentration-dependently inhibited CYPs1A, 2C8, 2C9, 2C19 and 3A in human liver microsomes (HLMs) in a reversible way, with IC 50 values varying from 1.06 μM to 3.43 μM. By contrast, MOA time-, concentrationand NADPH-dependently inhibited CYP2D6 and CYP2E1, along with K I and k inact values of 207 µM and 0.07 min -1 for CYP2D6, as well as 20.9 µM and 0.03 min -1 for CYP2E1. Further investigations demonstrated that a quinone metabolite of MOA could be trapped by GSH in a HLM incubation system, while CYPs2D6, 1A2 and 2E1 were the major contributors to catalyze the metabolic activation of MOA to the corresponding O-qunione intermediate.Additionally, the potential risks of herb-drug interactions triggered by MOA or MOA-related products were also predicted. Collectively, our findings verify that MOA is a reversible inhibitor of CYPs1A, 2C8, 2C9, 2C19 and 3A but acts as an inactivator of CYP2D6 and CYP2E1.

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