Investigation of Iminosugars as Antiviral Agents against SARS-CoV-2 Main Protease: Inhibitor Design and Optimization, Molecular Docking, and Molecular Dynamics Studies to Explore Potential Inhibitory Effect of 1-Deoxynojirmycin Series

Abstract

Background: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) poses an enormous challenge to human health and economy at a global level. According to WHO's latest data, till now, there have been a total of 641,435,884 confirmed cases of COVID-19, and the associated deaths are 6,621,060. Though few vaccinations have been approved for emergency usage, antiviral medications for long-term therapeutics are still being sought. The current research seeks to identify the inhibitory effect of iminosugars, particularly 1-deoxynojirmycin (IDNJ) series, against SARS-CoV-2 main protease (SARS-CoV2-Mpro) using an inhibitor optimization approach for 1DNJ series. Aim: The aim of this study was to investigate the inhibitory effect of iminosugars, specifically 1-deoxynojirmycin (1-DNJ) derivatives, on SARS-CoV-2 main protease (Mpro) as it plays a vital role in viral propagation and transcription and is shaped like a heart. Objective: The main objective of this study was to find the possibility of 1-DNJ derivatives being potent inhibitors against SARS CoV2 Mpro. This study was focused on finding the most probable conformation in which DNJ derivatives could bind to Mpro. Another objective was to obtain molecular-level details by getting insights into stable interactions formed between the ligand and receptor. Method: In silico molecular mechanics (MM) based techniques were employed to identify the best-docked inhibitors using molecular docking, and complexes that showed stable interactions were further subjected to 200 ns of molecular dynamics (MD) simulations to check the stability of ligand into the binding pocket of SARS-CoV2-Mpro. The inhibitors that formed stable complexes were further tested for their ADME properties in order to check the pharmacokinetic parameters as well as their therapeutic importance. Result: Docking was performed on 29 compounds from two different series against SARS-CoV-2 main protease, Mpro (PDB ID: 6LZE). Twelve compounds were found to have high docking scores and better interactions with the active site of Mpro, as compared to the co-crystallized ligand. Furthermore, the three highest-scoring docked compounds (17a, 7, and 8) depicted strong and stable complex formation, throughout the 200 ns molecular dynamics simulation, by analyzing the binding energy (MM/GBSA). The molecules were discovered to form stable interactions with conserved active-site residues, which play an important role in demonstrating activity in structure-based drug design. The ADMET analysis was performed using Qikprop, and the proposed stable derivatives passed all of the needed drug discovery standards, potentially inhibiting the Mpro of SARS-CoV-2. Conclusion: The present findings confer opportunities for compounds 17a, 7, and 8 that could be developed as new therapeutic agents against COVID-19. These compounds are suggested on the basis of pharmacokinetic parameters as well as therapeutic importance and hence could be tested in-vitro.