Discovery of Novel and Highly Potent Inhibitors of SARS CoV-2 Papain-Like Protease Through Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, Molecular Dynamics Simulations, and Biological Evaluation

Abstract

Background and Objective: COVID-19 has struck our society as a great calamity, and the need for effective anti-viral drugs is more urgent than ever. Papain-like protease (PLpro) of SARS CoV-2 plays important roles in virus maturation, dysregulation of host inflammation, and antiviral immune responses, which is being regarded as a promising druggable target for the treatment of COVID-19. Here, we carried out a combined screening approach to identify novel and highly potent PLpro inhibitors for the treatment of COVID-19.Methods: We used a combined screening approach of structure-based pharmacophore modeling and molecular docking to screen an in-house database containing 35,000 compounds. SARS CoV-2 PLpro inhibition assay was used to carry out the biological evaluation of hit compounds. Molecular dynamics (MD) simulations were conducted to check the stability of the PLpro-hit complexes predicted by molecular docking.Results: We found that four hit compounds showed excellent inhibitory activities against PLpro with IC50 values ranging from 0.6 to 2.4 μM. Among them, the most promising compound, hit 2 is the best PLpro inhibitor and its inhibitory activity was about 4 times higher than that of the positive control (GRL0617). The study of MD simulations indicated that four hits could bind stably to the active site of PLpro. Further study of interaction analysis indicated that hit 2 could form hydrogen-bond interactions with the key amino acids such as Gln269 and Asp164 in the PLpro-active site.Conclusion: Hit 2 is a novel and highly potent PLpro inhibitor, which will open the way for the development of clinical PLpro inhibitors for the treatment of COVID-19.

Discovery of PLpro and Mpro Inhibitors for SARS-CoV-2

“…53 A combination of pharmacophores and docking led to 4 low μM hits against PL pro although no antiviral activity was assessed. 54 A MedChemExpress library high throughput screen of 9791 compounds against PL pro led to three hits including the clinical candidate FXR agonist tropifexor 55 which was a low μM hit active in Calu-3 cells. A docking and structure-based design approach was used to identify indole dual inhibitors for PL pro and M pro with antiviral activity.…”

Virtual screening of substances used in the treatment of SARS-CoV-2 infection and analysis of compounds with known action on structurally similar proteins from other viruses

“… Target Docking software Molecular dynamics Drugs tested Promising anti-viral ligands Ref. 6W9C AutoDock Tools GROMACS Multiple drug databases MFCD00832476, MFCD02180753, Bemcentinib, Pacritinib Ergotamine [113] 7JN2 Maestro Desmond Database generated by AI integration A3659, A3777, A3777 [114] 7CMD MOE GROMACS In-house database contains 35,000 compounds Unnamed [115] 6WX4 Maestro AMBER 149 polyphenols Leucopelargonidin, Taxifolin, Morin, Eriodictyol, Myricetin, Enterodiol [116] 6WX4 YASARA YASARA 14,000 phytochemicals Baicalin, Hesperidin, Naringen, Flemiflavanone D, Euchrestaflavanone A [117] 7CJM AutoDock Vina AMBER FoodComEx database Triamterene, Estrone, Ibuprofen, Chlorpheniramine [118] 6W9C) AutoDock Tools GROMACS ChEBML database Azadirachtin-H Azadirachtin-I Azadirachtin-Q Azadirachtin [119] 7JN2 Glide Desmond SuperNatural Database ...…”

Identification of highly effective inhibitors against SARS-CoV-2 main protease: From virtual screening to in vitro study

“…ADMETlab web server (https://admetmesh.scbdd.com/) was used to predict the ADME properties of selected hits (Tian et al, 2022). The molecular weight (mol_MW), number of hydrogen bond acceptors (nHA), number of hydrogen bond donors (nHD), log of the octanol/water partition coefficient (logP), and log of the aqueous solubility (LogS) were evaluated.…”

“…According to a previously reported method (Tian et al, 2022), protein-hit complexes were investigated by molecular dynamics simulation using Groningen machine for chemical simulations software (GROMACS).…”

“…The quality of 3CL pro -model was validated using GH scoring method (Tian et al, 2022). The GH analysis were done by computing statistical parameters such as the enrichment factor (E) and goodness of hit score (GH).…”