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Discovery of Potential Antiviral Compounds and Accelerating the Therapeutic Discovery Against Monkeypox Virus

Title Page: Discovery of Potential Antiviral Compounds and Accelerating the Therapeutic Discovery Against Monkeypox Virus Faisal Ahmad1!*, Afifa Navid2!, Muhammad Irfan³, Fahad Nasser Almajhdi4, Tajamul Hussain5, Dilber Uzun Ozsahin6,7,8, Hassan Ayazº, Yasir Waheed10, 8, 11,12* ! These authors contributed equally and will be contributed as first authors. 1National University of Medical Sciences Rawalpindi, 46000, Pakistan, faisalahmad@bs.qau.edu.pk 2 Forman Christian College, University, Lahore 54600_afifanavid.bi@gmail.com, 3 ASRT, Inc., Atlanta, Georgia, 30080, USA, Irfanmuhammad299@gmail.com 4Botany and Microbiology Department, College of Science, King Saud University P.O.Box.2455, Riyadh 11451, Saudi Arabia. majndi@ksu.edu.sa 5Center of Excellence in Biotechnology Research, King Saud University, Riyadh 11451, Saudi Arabia. thussain@ksu.edu.pk 6Department of Medical Diagnostic Imaging, College of Health Sciences, Sharjah University, Sharjah, United Arab Emirate. dozsahin@sharjah.ac.ae 7Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arap Emirates Near East University, Operational Research Center in Healthcare, TRNC Mersin 10, Nicosia, 99138, Turkey 9Department of Biotechnology, Quaid-I-Azam University, Islamabad 45320, Pakistan. hassanayaz133@gmail.com 10NUST School of Health Sciences, National University of Sciences and Technology (NUST), H-12 Sector, Islamabad 44000, Pakistan. yasir_waheed_199@hotmail.com 11Széchenyi István University, Egyetem Square 1, H-9026 Győr, Hungary. 12University of Economics and Human Sciences in Warsaw, Warsaw 01-043, Poland.

Executive Summary: Monkeypox virus is a zoonotic virus of the genus Orthopox viruses. It can be transmitted through direct or indirect contact with animals or infected ones. Owing similarity of pathogenesis with smallpox, the same drugs can be used for both viruses, but they are not specific and only help to relieve the symptoms only. Therefore, the absence of antiviral treatment or licensed vaccine highlights an urgent need, especially due to its rapid prevalence. The study screened the library of compounds to retrieve drug-like molecules that can act against monkeypox virus. The highly virulent target gene B8R having uniport ID Q3I8J0 was chosen. Targeting B8R is substantial for global health and can align with SDG 3 and awareness of disease management. The B8R was modelled via Artificial intelligence (AI) AlphaFold method and then exposed to a library of compounds. Complementary interactions in the active site were shown by molecular docking. The Complex-1 had the greatest binding affinity (-8.4 kcal/mol), followed by Complex-2 (-8.1 kcal/mol) and Complex-3 (-7.7 kcal/mol). After 125 ns, Complex-1 reached equilibrium at 7.5 Å RMSD, according to MD simulations, exhibiting stable ligand retention and reliable interactions with crucial residues Gly135 and Lys136. Complex-3 shown intermediate protein stability (6 Å RMSD) but notable ligand fluctuation (48 Å RMSF), while Complex-2 displayed increased protein RMSD (8 Å RMSD) and delayed ligand stabilisation (16 Å RMSF). These results were corroborated by PCA analysis, which showed that Complex-1 exhibits coherent structural development whereas Complex-2 and Complex-3 show scattered and compact trajectories, respectively. Complex-1 promise for Mpox viral inhibition was highlighted by the fact that it was the most stable and dynamically favourable contender overall. The N-terminal follows the folding trend. The insilico analysis not only proposed a potent compound but also provides deep insight into the behavior of protein. The proposed potent compound against this zoonotic virus can be helpful to combat the monkeypox virus by subjecting it further towards experimental investigation.