Design of novel viral attachment inhibitors of the spike glycoprotein (S) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) through virtual screening and dynamics

Abstract

To date, the global COVID-19 pandemic has been associated with 11.8 million cases and over 545481 deaths. In this study, we have employed virtual screening approaches and selected 415 lead-like compounds from 103 million chemical substances, based on the existing drugs, from PubChem databases as potential candidates for the S protein-mediated viral attachment inhibition. Thereafter, based on drug-likeness and Lipinski's rules, 44 lead-like compounds were docked within the active side pocket of the viral-host attachment site of the S protein. Corresponding ligand properties and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile were measured. Furthermore, four novel inhibitors were designed and assessed computationally for efficacy. Comparative analysis showed the screened compounds in this study maintain better results than the proposed mother compounds, VE607 and SSAA09E2. The four designed novel lead compounds possessed more fascinating output without deviating from any of Lipinski's rules. They also showed higher bioavailability and the drug-likeness score was 0.56 and 1.81 compared with VE607 and SSAA09E2, respectively. All the screened compounds and novel compounds showed promising ADMET properties. Among them, the compound AMTM-02 was the best candidate, with a docking score of -7.5 kcal/mol. Furthermore, the binding study was verified by molecular dynamics simulation over 100 ns by assessing the stability of the complex. The proposed screened compounds and the novel compounds may give some breakthroughs for the development of a therapeutic drug to treat SARS-CoV-2 proficiently in vitro and in vivo.

Keywords: ADMET; Drug designing; Molecular docking; Molecular dynamics; Virtual screening.

Figure 1

Phylogenetic tree analysis of the retrieved sequences of spike glycoprotein (S).

Figure 2

Multiple sequence alignment of the selected proteins. Receptor-binding domain (RBD) is shown with appropriate conservation at the bottom (yellow).

Figure 2

Multiple sequence alignment of the selected proteins. Receptor-binding domain (RBD) is shown with appropriate conservation at the bottom (yellow).

Figure 3

Schematic representation of the major domain and motif structure of the spike glycoprotein (S). The S1 subunit contains NTD (14–305 aa), RBD (319–541 aa), and RBM (437–508 aa). The S2 subunit contains HR1 (912–984 aa), and HR2 (1163–1213 aa).

Figure 4

Homology model, structural evaluation, and domain organization. The three-dimensional model of the targeted protein (surface view) is showed in 4a. In 4b, the superposition between the predicted model (cyan color) and template (blue color) 6VSB_A is presented with RMSD of 0.202. The Ramachandran plot validation of the predicted model, where 95.06% amino-acid residues are in the most favored region, is depicted in 4c. The receptor-binding domain (RBD) (red sphere) (4d) and the receptor-binding motif (RBM) (cyan sphere) (4e) is the main catalytic site for the binding with host surface protein. The amino acid residues of the RBM are shown in 4e (zoomed view).

Figure 5

Electrostatic potentiality of the targeted protein. Energy distributions are shown before minimization in 5a and after minimization in 5b. In the energy distribution, blue color (positive charges) indicates higher energy and red color (negative charges) indicates lower energy potentiality. White color indicates energy neutral status.

Figure 6

Active sites of the predicted protein. The large two volumes of the active sites are depicted here. In 6a (blue sphere), is the large cavity of the active site and in 6b (red sphere), the second large volume of the active site cavity is depicted.

Figure 7

Molecular docking interaction analysis. All the ligands are docked into the active site pocket of the protein and different ligands are shown by different colors (7a). Interacting amino acid residues of the protein with different ligands (including VE607 and SSAA09E2) (7b). The interaction descriptions are shown graphically in the bottom of 7b.

Figure 7

Molecular docking interaction analysis. All the ligands are docked into the active site pocket of the protein and different ligands are shown by different colors (7a). Interacting amino acid residues of the protein with different ligands (including VE607 and SSAA09E2) (7b). The interaction descriptions are shown graphically in the bottom of 7b.

Figure 7

Molecular docking interaction analysis. All the ligands are docked into the active site pocket of the protein and different ligands are shown by different colors (7a). Interacting amino acid residues of the protein with different ligands (including VE607 and SSAA09E2) (7b). The interaction descriptions are shown graphically in the bottom of 7b.

Figure 7

Molecular docking interaction analysis. All the ligands are docked into the active site pocket of the protein and different ligands are shown by different colors (7a). Interacting amino acid residues of the protein with different ligands (including VE607 and SSAA09E2) (7b). The interaction descriptions are shown graphically in the bottom of 7b.

Figure 8

Designed novel lead and molecular docking interaction analysis. Newly designed novel leads are shown in 8a. All the novel leads are docked into the active site pocket of the protein and different leads are shown by different colors (zoomed view) (8b). Interacting amino acid residues of the proteins with different ligands (8c). The interaction descriptions are shown graphically in the bottom of 8c.

Figure 9

Molecular dynamics simulations of the targeted protein and the protein–ligand (AMTM-02) complex. In 9a, the time series of the RMSD of backbone atoms (C, Cα, and N) for protein. Here, red and blue lines denote Apo_QHR63290, and QHR63290-Ligand complex, respectively. In 9b, the structural changes of protein using root means square fluctuations (RMSF) analysis. Here, red, and blue lines denote Apo_QHR63290, and QHR63290-Ligand complex, respectively. The looped structures of the fluctuated residues are represented in the extended view.