High-throughput virtual screening of drug databanks for potential inhibitors of SARS-CoV-2 spike glycoprotein

Abstract

COVID-19, which is caused by a novel coronavirus known as SARS-CoV-2, has spread rapidly around the world, and it has infected more than 29 million individuals as recorded on 16 September 2020. Much effort has been made to stop the virus from spreading, and there are currently no approved pharmaceutical products to treat COVID-19. Here, we apply an in silico approach to investigate more than 3800 FDA approved drugs on the viral RBD S 1 -ACE2 interface as a target. The compounds were investigated through flexible ligand docking, ADME property calculations and protein–ligand interaction maps. Molecular dynamics (MD) simulations were also performed on eleven compounds to study the stability and the interactions of the protein–ligand complexes. The MD simulations show that bagrosin, chidamide, ebastine, indacaterol, regorafenib, salazosulfadimidine, silodosin and tasosartan are relatively stable near the C terminal domain (CTD1) of the S 1 subunit of the viral S protein. The relative MMGBSA binding energies show that silodosin has the best binding to the target. The constant velocity steered molecular dynamics (SMD) simulations show that silodosin preferentially interacts with the RBD S 1 and has potential to act as an interfering compound between viral spike–host ACE2 interactions. Communicated by Ramaswamy H. Sarma

Prediction of repurposed drugs for Coronaviruses using artificial intelligence and machine learning

“…It also provides the information about the interaction and reactivity of the molecules as potential drug candidates [42] . Few literature reports have identified the repurposed drugs that targets SARS-CoV-2 Spike protein [43] , [44] , [45] . Current study identifies 06 ligands molecules with high binding affinity, i.e.Verteporfin, Alatrofloxacin, Metergoline, Rescinnamine, Leuprolide, Telotristat ethyl against the SARS-CoV-2 S-protein complex with ACE receptor.…”

“…To find the minimum binding affinity the exhaustiveness parameter was set 10. The ligand and protein molecules interacting residues were analysed using Pymol [44] and Discovery Studio Visualizer [69] .…”

Combined use of the hepatitis C drugs and amentoflavone could interfere with binding of the spike glycoprotein of SARS-CoV-2 to ACE2: the results of a molecular simulation study

“…A large number of drug-repurposing studies are focused on the spike–ACE2 interaction surface (Alazmi & Motwalli, 2020 ; Awad et al, 2020 ; de Oliveira et al, 2020 ; Deganutti et al, 2021 ; Hakmi et al, 2020 ; Tao et al, 2021 ; Trezza et al, 2020 ; Unni et al, 2020 ; Wei et al, 2020 ). There are also studies searching for inhibitors for RNA-dependent RNA polymerase (Elfiky, 2020 ), papain-like protease (Ibrahim et al, 2020 ), and RNA endoribonuclease (Khan, Jha, Singh, et al, 2020 ; Sharma et al, 2021 ).…”

Accelerating the Discovery of the Beyond Rule of Five Compounds That Have High Affinities Toward SARS-CoV-2 Spike RBD

“…Different approaches have been conducted that are based on interfering with the RBD binding to the hACE2 including neutralizing antibodies, [24][25][26] miniproteins, 27 peptides, [28][29][30] and small molecules. [31][32][33][34][35] As far as we are aware, no high-throughput virtual screening has been conducted in relatively large molecules in the "beyond rule of 5" chemical space that have high RBD binding affinity. Herein, we performed a comprehensive computational protocol, which incorporates molecular docking, MD simulations, absolute binding energy cal-culations, and steered MD simulations for the discovery of relatively large compounds that would bind to SARS-CoV-2 spike RBD very tightly, therefore, blocking viral attachment to the host cell.…”