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Eman G Haggag,1 Ali M Elshamy,2 Mohamed A Rabeh,2,3 Nagwan M Gabr,1 Mohamed Salem,4 Khayrya A Youssif,3 Ahmed Samir,4 Abdullatif Bin Muhsinah,5 Abdulrhman Alsayari,5 Usama Ramadan Abdelmohsen61Department of Pharmacognosy, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt; 2Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; 3Department of Pharmacognosy, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt; 4Department of Pharmaceutical Chemistry, October University for Modern Sciences and Arts (Msa), Cairo, Egypt; 5Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 61441, Saudi Arabia; 6Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia, EgyptBackground: Viral and microbial infections constitute one of the most important life-threatening problems. The emergence of new viral and bacterial infectious diseases increases the demand for new therapeutic drugs.Purpose: The objective of this study was to use the aqueous and hexane extracts of Lampranthus coccineus and Malephora lutea F. Aizoaceae for the synthesis of silver nanoparticles, and to investigate its possible antiviral activity. In addition to the investigation of the phytochemical composition of the crude methanolic extracts of the two plants through UPLC-MS metabolomic profiling, and it was followed by molecular docking in order to explore the chemical compounds that might contribute to the antiviral potential.Methods: The formation of SNPs was further confirmed using a transmission electron microscope (TEM), UV-Visible spectroscopy and Fourier transform infrared spectroscopy. The antiviral activity of the synthesized nanoparticles was evaluated using MTT assay against HSV-1, HAV-10 virus and Coxsackie B4 virus. Metabolomics profiling was performed using UPLC-MS and molecular docking was performed via Autodock4 and visualization was done using the Discovery studio.Results: The early signs of SNPs synthesis were detected by a color change from yellow to reddish brown color. The TEM analysis of SNPs showed spherical nanoparticles with mean size ranges between 10.12 nm to 27.89 nm, and 8.91 nm 14.48 nm for Lampranthus coccineus and Malephora lutea aqueous and hexane extracts respectively. The UV-Visible spectrophotometric analysis showed an absorption peak at λmax of 417 nm.The green synthesized SNPs of L. coccineus and M. lutea showed remarkable antiviral activity against HSV-1, HAV-10, and CoxB4 virus. Metabolomics profiling of the methanolic extract of L. coccineus and M. lutea resulted in identifying 12 compounds. The docking study predicted the patterns of interactions between the compounds of L. coccineus and M. lutea with herpes simplex thymidine kinase, hepatitis A 3c proteinase, and Coxsackievirus B4 3c protease, which was similar to those of the co-crystal inhibitors and this can provide a supposed explanation for the antiviral activity of the aqueous and nano extracts of L. coccineus and M. lutea.Conclusion: These results highlight that SNPs of L. coccineus and M. lutea could have antiviral activity against HSV-1, HAV-10, and CoxB4 virus.Keywords: silver nanoparticles, antiviral, metabolomics profiling, Lampranthus coccineus, Malephora lutea