Antiviral drug discovery by targeting the SARS-CoV-2 polyprotein processing by inhibition of the main protease

Abstract

The spread of SARS-CoV-2, the causative agent for COVID-19, has led to a global and deadly pandemic. To date, few drugs have been approved for treating SARS-CoV-2 infections. In this study, a structure-based approach was adopted using the SARS-CoV-2 main protease (Mpro) and a carefully selected dataset of 37,060 compounds comprising Mpro and antiviral protein-specific libraries. The compounds passed two-step docking filtration, starting with standard precision (SP) followed by extra precision (XP) runs. Fourteen compounds with the highest XP docking scores were examined by 20 ns molecular dynamics simulations (MDs). Based on backbone route mean square deviations (RMSD) and molecular mechanics/generalized Born surface area (MM/GBSA) binding energy, four drugs were selected for comprehensive MDs analysis at 100 ns. Results indicated that birinapant, atazanavir, and ritonavir potently bound and stabilized SARS-CoV-2 Mpro structure. Binding energies higher than −102 kcal/mol, RMSD values <0.22 nm, formation of several hydrogen bonds with Mpro, favourable electrostatic contributions, and low radii of gyration were among the estimated factors contributing to the strength of the binding of these three compounds with Mpro. The top two compounds, atazanavir and birinapant, were tested for their ability to prevent SARS-CoV-2 plaque formation. At 10 µM of birinapant concentration, antiviral tests against SARS-CoV-2 demonstrated a 37% reduction of virus multiplication. Antiviral assays demonstrated that birinapant has high anti-SARS-CoV-2 activity in the low micromolar range, with an IC50 value of 18 ± 3.6 µM. Therefore, birinapant is a candidate for further investigation to determine whether it is a feasible therapy option.

The Outcomes of Sodium-Glucose Co-transporter 2 Inhibitors (SGLT2I) on Diabetes-Associated Neuropathy: A Systematic Review and meta-Analysis

“…Computational tools and meta-analysis are gold standards in diseases epidemiology, treatment and control ( Kandeel et al, 2021 ; Kandeel and El-Deeb, 2022a ; Kandeel and El-Deeb, 2022b ; Burayk et al, 2022 ; Kandeel et al, 2022 ; Kim et al, 2022 ). DN is the most encountered microvascular complication of diabetes.…”

A Diversifiable Synthetic Platform for the Discovery of New Carbasugar SGLT2 Inhibitors Using Azide–Alkyne Click Chemistry

“…Molecular Docking Study Docking investigations, protein and chemical preparations were carried out in accordance with earlier descriptions. 30,31) The compounds' 2 dimensional (2D) structures were imported and 3D optimized by LigPrep software using the OPLS2005 force field. The protein preparation wizard in the Maestro suite (Schrodinger LLC, NY, U.S.A.) was used to process and optimize the SGLT2 structure (PDB ID 7vsi).…”

Alpha and gamma mangostins inhibit wild-type B SARS-CoV-2 more effectively than the SARS-CoV-2 variants and the major target is unlikely the 3C-like protease

“…Moreover, several reports suggested natural products as potential inhibitors, with one of the most common targets being 3CL pro [ [6] , [7] , [8] , [9] , [10] , [11] ]. Alpha, gamma-mangostins (AM and GM), and their derivatives were previously characterized as potential 3CL pro inhibitors based on an in silico study [ 8 , [11] , [12] , [13] , [14] ]. These compounds were also reported as an angiotensin converting enzyme (ACE)-2 binding inhibitor [ 15 ].…”