Rational design of potent anti-COVID-19 main protease drugs: An extensive multi-spectrum in silico approach

Abstract

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a novel coronavirus and the etiological agent of global pandemic coronavirus disease (COVID-19) requires quick development of potential therapeutic strategies. Computer aided drug design approaches are highly efficient in identifying promising drug candidates among an available pool of biological active antivirals with safe pharmacokinetics. The main protease (M Pro ) enzyme of SARS-CoV-2 is considered key in virus production and its crystal structures are available at excellent resolution. This marks the enzyme as a good starting receptor to conduct an extensive structure-based virtual screening (SBVS) of ASINEX antiviral library for the purpose of uncovering valuable hits against SARS-CoV-2 M Pro . A compound hit (BBB_26580140) was stand out in the screening process, as opposed to the control, as a potential inhibitor of SARS-CoV-2 M Pro based on a combined approach of SBVS, drug likeness and lead likeness annotations, pharmacokinetics, molecular dynamics (MD) simulations, and end point MM-PBSA binding free energy methods. The lead was further used in ligand-based similarity search (LBSS) that found 33 similar compounds from the ChEMBL database. A set of three compounds (SCHEMBL12616233, SCHEMBL18616095, and SCHEMBL20148701), based on their binding affinity for M Pro , was selected and analyzed using extensive MD simulation, hydrogen bond profiling, MM-PBSA, and WaterSwap binding free energy techniques. The compounds conformation with M Pro show good stability after initial within active cavity moves, a rich intermolecular network of chemical interactions, and reliable relative and absolute binding free energies. Findings of the study suggested the use of BBB_26580140 lead and its similar analogs to be explored in vivo which might pave the path for rational drug discovery against SARS-CoV-2 M Pro .

In Silico Models for Anti-COVID-19 Drug Discovery: A Systematic Review

“…SARS-CoV-2 M pro was already mentioned as the most common drug target. Several researchers used it in their studies as the preferred drug target, including Ghosh et al [ 14 ]; Kumari et al [ 16 ]; Ibrahim et al [ 20 ]; Ibrahim et al [ 21 ]; Rivero Segura and Gomez-Verjan [ 23 ]; Ibrahim et al, [ 27 ]; Feng et al, [ 31 ]; Adem et al, [ 33 ]; Elkaeed et al, [ 34 ]; Ibrahim et al, [ 35 ]; Ahmad et al, [ 36 ]; Ibrahim et al, [ 39 ]; and Aleissa et al, [ 40 ]. All these researchers used SARS-CoV-2 M pro as the sole drug target and discovered different lead compounds that could be used as anti-COVID-19 drugs.…”

Endophytic bacteria of Fagonia indica Burm. f revealed to harbour rich secondary antibacterial metabolites

“…The crystal structure of the mentioned proteins was retrieved from protein data bank (PDB) and prepared in UCSF Chimera version where any associated ligand molecules, as well as water molecules, were removed. Each protein was also minimized for 1000 rounds (500 steepest descent and 500 conjugate gradient steps) [ 14 ]. Both the receptors and the compounds were then used as input for docking studies in AutoDock 4.2.…”

Me-Better Drug Design Based on Nevirapine and Mechanism of Molecular Interactions with Y188C Mutant HIV-1 Reverse Transcriptase

“…After hydrogenation and energy optimization of NVP, fragment growth was generated by protocol of De Novo Evolution based on receptor–ligand interaction [ 25 , 26 ]. Referring to publications [ 27 , 28 , 29 ], these new ligands were added fragments without changing binding site inside Y188CM-RT, named Lig 1 to Lig 10, respectively.…”

“…Molecular dynamics simulation can verify the binding affinity between Y188CM-RT and NVP-based ligands [ 29 , 30 ]. The process was implemented by DS 2016 as follows: (1) we deleted redundant peptides, prepared a structure and applied a CHARm force field.…”