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Liuwei Kangguan Formula: Mechanism-driven and computation-assisted optimization from Xuanfei Baidu Formula for
Sijia Yu1, Bin Liu2, Xuanxuan Li2
1Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Objective:
To advance mechanism-driven optimization of traditional Chinese medicine (TCM) formulas for modern drug development, a computation assisted strategy integrating multiple reporter assays with network topology analysis was proposed. The strategy was applied to simplify Xuanfei Baidu Formula (XFBD), a clinically approved anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), to generate the optimized Liuwei Kangguan Formula (LWKG).
Methods:
An integrated transcriptomic analysis of public corona virus disease 2019 (COVID-19) datasets was applied to identify core targets. Reporter models evaluating these targets were established and evaluated through time-sequential agonist exposure and chemical interferences. These models were then used to screen for active components in XFBD, based on which a formula-herb-compound tripartite network was constructed and analyzed with seven topological algorithms. The prioritized nodes guided the formulation of the optimized preparation, LWKG. LWKG was then evaluated through chemical profiling and pharmacological experiments.
Results:
Transcriptomic analysis identified nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and interferon-stimulated response element (ISRE) as key transcriptional regulators mediating anti-SARS-CoV-2 immune responses. Triple reporter models were then constructed, which demonstrated temporal activation and crosstalk among the three pathways. Subsequently, 20 serum-available compounds and nine herbal extracts were identified as potential active substances from 77 tested substances of XFBD, and six core components were prioritized to prepare LWKG. LWKG retained 62.1% of phytochemical features in XFBD. Besides, it demonstrated pharmacological activities in modulating antiviral innate immunity, inhibiting replication of SARS-CoV-2 subtypes, and alleviating pneumonia in SARS-CoV-2 or human coronavirus OC43 (HCoV-OC43) infected mice.
Conclusion:
Through our strategy the composition of XFBD was simplified while maintaining immunomodulatory and antiviral efficacy. This study provided a feasible framework combining wet-lab and in silico experiments for optimizing TCM formulas.
