A molecular modelling approach for identifying antiviral selenium-containing heterocyclic compounds that inhibit the main protease of SARS-CoV-2: an in silico investigation

Abstract

Coronavirus disease 2019 (COVID-19), an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic by the World Health Organization, and the situation worsens daily, associated with acute increases in case fatality rates. The main protease (Mpro) enzyme produced by SARS-CoV-2 was recently demonstrated to be responsible for not only viral reproduction but also impeding host immune responses. The element selenium (Se) plays a vital role in immune functions, both directly and indirectly. Thus, we hypothesised that Se-containing heterocyclic compounds might curb the activity of SARS-CoV-2 Mpro. We performed a molecular docking analysis and found that several of the selected selenocompounds showed potential binding affinities for SARS-CoV-2 Mpro, especially ethaselen (49), which exhibited a docking score of −6.7 kcal/mol compared with the −6.5 kcal/mol score for GC376 (positive control). Drug-likeness calculations suggested that these compounds are biologically active and possess the characteristics of ideal drug candidates. Based on the binding affinity and drug-likeness results, we selected the 16 most effective selenocompounds as potential anti-COVID-19 drug candidates. We also validated the structural integrity and stability of the drug candidate through molecular dynamics simulation. Using further in vitro and in vivo experiments, we believe that the targeted compound identified in this study (ethaselen) could pave the way for the development of prospective drugs to combat SARS-CoV-2 infections and trigger specific host immune responses.

Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm

“…During an episode of ARDS, the titer values of proinflammatory cytokines and chemokines are soared up, along with high viral titers. High concentrations of interleukins (IL-1B), IFNs (IFN-γ), monocyte chemoattractant protein (MCP-1), and IFN-induced proteins (IP-10) have been identified in patients with COVID-19 [ 68 ]. The release of these specific cytokines is likely to activate the T-helper-1 (Th-1) cells, which elicit specific immunity [ 68 , 69 ].…”

“…High concentrations of interleukins (IL-1B), IFNs (IFN-γ), monocyte chemoattractant protein (MCP-1), and IFN-induced proteins (IP-10) have been identified in patients with COVID-19 [ 68 ]. The release of these specific cytokines is likely to activate the T-helper-1 (Th-1) cells, which elicit specific immunity [ 68 , 69 ]. During SARS-CoV-2 infection, these specific cytokines also activate T-helper-2 cell cytokines (IL4 and 10) that cause a negative inflammatory response, leading to more disease severity [ 70 ].…”

Diverse Immunological Factors Influencing Pathogenesis in Patients with COVID-19: A Review on Viral Dissemination, Immunotherapeutic Options to Counter Cytokine Storm and Inflammatory Responses

“…Age alone is an important bifurcation criterion in COVID-19 susceptibility [174,175]. The geriatric populations succumb to other risk factors such as hyperlipidemia, hyperglycemia, cardiovascular diseases, and lung diseases [176]. The lethal combination of age-related immune dysregulation and co-morbid conditions causes the unregulated release of cytokines.…”

Prospective Role of Peptide-Based Antiviral Therapy Against the Main Protease of SARS-CoV-2

“…The simulation was run by using 1.25 fs time step. The trajectories were saved after every 100 ps to analyze the root mean square deviation, root mean square fluctuations, hydrogen bond, radius of gyration, and solvent accessible surface area (Bappy et al, 2020;Khan et al, 2020;Islam et al, 2020;Mahmud et al, 2020a;Mahmud et al, 2020b;Mahmud et al, 2021b;Swargiary et al, 2020;Chowdhury et al, 2021;Rakib et al, 2021;Uddin et al, 2021).…”