Abstract: Repositioning Therapeutics for COVID-19: Virtual Screening of the Potent Synthetic and Natural Compounds as SARS-CoV-2 3CLpro Inhibitors Ahmad Sattari University of Zanjan Ali Ramazani (  aliramazani@gmail.com ) University of Zanjan Hamideh Aghahosseini University of Zanjan Research Article Keywords: COVID-19, Drug discovery, Medicinal chemistry, Molecular docking, Synthetic and natural ligands Posted Date: June 30th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-37994/v1 License:   This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Version of Record: A version of this preprint was published at Journal of the Iranian Chemical Society on March 26th, 2021. See the published version at https://doi.org/10.1007/s13738-021-02235-7. Page 1/31 Abstract Today, finding potential therapeutics for COVID-19 caused by the widespread transmission of SARS-CoV-2 has become a global challenge. Molecular docking investigation of the therapeutic potential of marketed drugs is a fast and cost effective approach to provide a solution to this problem. In this study, docking simulations performed on the reported structure of the virus main protease, 3CLpro, to identify potential inhibitors. Accordingly, a database of 50 synthetic compounds including approved drugs and those undergoing clinical trials, and 40 natural compounds particularly those employed in traditional Iranian medicine was constructed. The results indicated that the anti-inflammatory drugs, Licofelone acyl glucuronide and delta-bilirubin, and natural compounds such as kappa-carrageenan conformer and beta- D-galactopyranosyl with minimal side-effects, according to in-vitro studies, are good candidates to block the enzymatic activity of SARS-CoV-2 3CLpro. Moreover, the compound 1 could be a potential drug candidate for COVID-19 due to its favorable interactions with the 3CLpro.