Identification of high-affinity inhibitors of SARS-CoV-2 main protease: Towards the development of effective COVID-19 therapy

Mohammad, Taj; Shamsi, Anas; Anwar, Saleha; Hussain, Afzal; Rehman, Md. Tabish; AlAjmi, Mohamed F.; Islam, Asimul; Hassan, Md. Imtaiyaz

Coronavirus disease 2019 (COVID-19) is an infectious disease, caused by a newly emerged highly pathogenic virus called novel severe acute respiratory syndrome coronavirus (SARS-CoV-2). Targeting the main protease (M(pro), 3CL(pro)) of SARS-CoV-2 is a justified approach for drug development because this enzyme plays a significant role in the viral replication and transcription. The available crystal structures of SARS-CoV-2 M(pro) determined in the presence of different ligands and inhibitors-like compounds provide a platform for the quick development of selective inhibitors of SARS-CoV-2 M(pro). In this study, we utilized the structural information of co-crystallized SARS-CoV-2 M(pro) for the structure-guided drug discovery approach to finding high-affinity inhibitors from the PubChem database. The screened compounds were selected on the basis of their physicochemical properties, drug-likeliness, and strength of affinity to the SARS-CoV-2 M(pro). Finally, we have identified 6-Deaminosinefungin (PubChem ID: 10428963) and UNII-O9H5KY11SV (PubChem ID: 71481120) as potential inhibitors of SARS-CoV-2 M(pro) which may be further exploited in drug development to address SARS-CoV-2 pathogenesis. Both compounds are structural analogs of known antiviral compounds, having considerable protease inhibitory potential with improved pharmacological properties. All-atom molecular dynamics simulations suggested SARS-CoV-2 M(pro) in complex with these compounds is stable during the simulation period with minimal structural changes. This work provides enough evidence for further implementation of the identified compounds in the development of effective therapeutics of COVID-19.