Abstract: ARTICLE https://doi.org/10.1038/s42003-020-01577-x OPEN 1234567890():,; Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents Vicky Mody1,3, Joanna Ho1, Savannah Wills1, Ahmed Mawri1, Latasha Lawson1, Maximilian C. C. J. C. Ebert2, Guillaume M. Fortin2, Srujana Rayalam1 & Shashidharamurthy Taval 1,3 ✉ Emerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARSCoV-2 specific drugs. Herein, we have identified potential drugs that target the 3chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARSCoV-2 viral targets. of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine – Georgia Campus, Suwanee, GA, USA. Computing Group, 910-1010 Sherbrooke W, Montreal, QC H3A 2R7, Canada. 3These authors contributed equally: Vicky Mody, Shashidharamurthy Taval. ✉email: rangaiahsh@pcom.edu 1 Department 2 Chemical COMMUNICATIONS BIOLOGY | (2021)4:93 | https://doi.org/10.1038/s42003-020-01577-x | www.nature.com/commsbio 1 ARTICLE T COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-020-01577-x he major pandemic outbreak of the 21st century due to severe acute respiratory syndrome coronavirus-2 (SARSCoV-2) has become a global threat to public health because of its high rate of infection leading to mortality. As of 24 December 2020, there are a total of 13,881,620 COVID-19 positive cases and 272,820 deaths in the United States alone and 64,326,880 confirmed cases and 1,488,992 deaths globally (https:// coronavirus.jhu.edu/). The death toll is increasing at an alarming rate because of the lack of COVID-19 specific drugs or vaccines. Development, validation, and approval of COVID-19 specific drugs takes years1. Therefore, the idea of drug repositioning, also known as repurposing, is an important strategy to control the sudden outbreak of life-threatening infectious agents that spread rapidly. FDA approved anti-viral drugs are known to be safe for use in humans2, but their effectiveness against SARS-CoV-2 needs to be experimentally validated. Several FDA approved antiviral drugs such as favipiravir, danoprevir, darunavir, lopinavir, oseltamivir, ritonavir, remdesivir, and umifenovir are in clinical trials to study anti-COVID-19 activity3. However, the effectiveness of these drugs for preventing or reducing the severity of symptoms of COVID-19 has not yet been completely established. Therefore, there is an urgent need to identify additional drug candidates to target different SARS-CoV-2 proteins for enhanced efficacy in the treatment of COVID-19. Recently, Wu et al.4 sequenced and compared SARS-CoV-2 genome with other..