A systems pharmacology framework for developing Ayurveda herbal formulations against COVID-19

Abstract

Traditional Ayurvedic formulations have demonstrated therapeutic potential in alleviating COVID-19 symptoms; however, their multitarget mechanisms remain insufficiently characterized. In this study, a comprehensive systems pharmacology framework was developed to unravel the molecular mechanisms and therapeutic relevance of six Ayurvedic formulations clinically used against SARS-CoV-2. A multi-layered interactome was constructed by integrating virus–host-microbiota interactions, phytochemical constituents, and their medicinal plant origins. Bioactive compounds were filtered based on ADME parameters (oral bioavailability ≥30 %, drug-likeness ≥0.18), and their targets were predicted using STITCH, followed by molecular docking against key SARS-CoV-2 proteins (3CLpro, PLpro, and RdRp). The resulting network comprised 2315 nodes and 3859 edges, mapping 159 compounds to 1494 human targets. Functional enrichment revealed significant associations with lipid metabolism (p = 1.8 × 10⁻⁵), inflammation (p = 6.1 × 10⁻⁶), and immune regulatory pathways involving IL-10 and TBK1. Docking simulations identified 44 phytochemicals from 22 plants with strong binding affinities (ΔG = –7.5 to –9.2 kcal/mol) to viral proteins. Among them, Zingiber officinale emerged as the top-ranked herb, contributing 12 bioactive compounds, including 6-shogaol, 6-gingerol, curcumin, and rutin, which modulate both viral and host targets, such as SCARB1, COMT, and GNB1. The ADME evaluation further validated compounds such as apigenin, piperine, and ferulic acid for their high gastrointestinal absorption (>85 %) and drug-likeness, supporting the viability of oral formulations. Overall, this integrative framework highlights Z. officinale, Ocimum sanctum, Pterocarpus marsupium, and Momordica charantiaas key candidates for multicomponent COVID-19 therapy and provides a mechanistic foundation for their advancement into preclinical and clinical research.