Targeting SARS-CoV-2 main protease: structure based virtual screening, in silico ADMET studies and molecular dynamics simulation for identification of potential inhibitors

Abstract

COVID-19 pandemic has created a healthcare crisis across the world and has put human life under life-threatening circumstances. The recent discovery of the crystallized structure of the main protease (M_pro) from SARS-CoV-2 has provided an opportunity for utilizing computational tools as an effective method for drug discovery. Targeting viral replication has remained an effective strategy for drug development. M_pro of SARS-COV-2 is the key protein in viral replication as it is involved in the processing of polyproteins to various structural and nonstructural proteins. Thus, M_pro represents a key target for the inhibition of viral replication specifically for SARS-CoV-2. We have used a virtual screening strategy by targeting M_pro against a library of commercially available compounds to identify potential inhibitors. After initial identification of hits by molecular docking-based virtual screening further MM/GBSA, predictive ADME analysis, and molecular dynamics simulation were performed. The virtual screening resulted in the identification of twenty-five top scoring structurally diverse hits that have free energy of binding (ΔG) values in the range of -26-06 (for compound AO-854/10413043) to -59.81 Kcal/mol (for compound 329/06315047). Moreover, the top-scoring hits have favorable AMDE properties as calculated using in silico algorithms. Additionally, the molecular dynamics simulation revealed the stable nature of protein-ligand interaction and provided information about the amino acid residues involved in binding. Overall, this study led to the identification of potential SARS-CoV-2 M_pro hit compounds with favorable pharmacokinetic properties. We believe that the outcome of this study can help to develop novel M_pro inhibitors to tackle this pandemic.Communicated by Ramaswamy H. Sarma.

Keywords: SARS-COV-2; Virtual screening; anti-viral; hit identification; in silico ADME; main protease; molecular dynamics.

Figure 1.

The overall workflow of virtual screening and analysis.

Figure 2.

Two-dimensional structures of top twenty-five hits identified through structure-based virtual screening.

Figure 3.

Three-dimentional binding pose and two-dimentional ligand interaction diagram of co-crystalized ligand, Z31792168 (A) and top hit AG-690/11060013 (B).

Figure 4.

Three-dimentional binding pose and two-dimentional ligand interaction diagram of hits AG-690/11203374_1 (A) and AG-690/11203374_2 (B).

Figure 5.

Three-dimentional binding pose and two-dimentional ligand interaction diagram of hits AG-690/11203374_3 (A) and AH-034/04857012 (B).

Figure 6.

Molecular dynamics trajectory analysis of AG-690/11060013 (A) RMSD of the protein and ligand with respect to the first frame (B) Protein RMSF (C) Protein-ligand contacts histogram (D) Ligand RMSF (E) Ligand-protein contacts (F) Protein-ligand contacts.

Figure 7.

Molecular dynamics trajectory analysis of AG-690/11203374_1 (A) RMSD of the protein and ligand with respect to the first frame (B) Protein RMSF (C) Protein-ligand contacts histogram (D) Ligand RMSF (E) Ligand-protein contacts (F) Protein-ligand contacts.

Figure 8.

Molecular dynamics trajectory analysis of AG-690/11203374_2 (A) RMSD of the protein and ligand with respect to the first frame (B) Protein RMSF (C) Protein-ligand contacts histogram (D) Ligand RMSF (E) Ligand-protein contacts (F) Protein-ligand contacts.

Figure 9.

Molecular dynamics trajectory analysis of AG-690/11203374_3 (A) RMSD of the protein and ligand with respect to the first frame (B) Protein RMSF (C) Protein-ligand contacts histogram (D) Ligand RMSF (E) Ligand-protein contacts (F) Protein-ligand contacts.

Figure 10.

Molecular dynamics trajectory analysis of AH-034/04857012 (A) RMSD of the protein and ligand with respect to the first frame (B) Protein RMSF (C) Protein-ligand contacts histogram (D) Ligand RMSF (E) Ligand-protein contacts (F) Protein-ligand contacts.