Abstract
BACKGROUND: The main protease (Mpro) of SARS-CoV-2 is involved in the processing of vital polypeptides required for viral genome replication and transcription and is one of the best-characterized targets to inhibit the progression of SARS-CoV-2 in infected individuals. METHODS: We screened a set of novel classes of acridinediones molecules to efficiently bind and inhibit the activity of the SARS-CoV-2 by targeting the Mpro. The repurposed FDA-approved antivirals were taken as standard molecules for this study. Long term (1.1 μs) MD simulations were performed to analyze the conformational space of the binding pocket of Mpro bound to the selected molecules. RESULTS: The molecules DSPD-2 and DSPD-6 showed more favorable MM-PBSA interaction energies and were seated more deeply inside the binding pocket of Mpro than the topmost antiviral drug (Saquinavir). Moreover, DSPD-5 also exhibited comparable binding energy to Saquinavir. The analysis of per residue contribution energy and SASA studies indicated that the molecules showed efficient binding by targeting the S1 subsite of the Mpro binding pocket. CONCLUSION: The DSPD-2, DSPD-6, and DSPD-5 could be developed as potential inhibitors of SARS-CoV-2. Moreover, we suggest that targeting molecules to bind effectively to the S1 subsite could potentially increase the binding of molecules to the SARS-CoV-2 Mpro.