Fig 1.
Pathology of COVID-19 displaying the development of neurological disorder.
Fig 2.
Portrayal of representative examples from the selected data set (five most active 1–5 and five 102–106 least active molecules).
Fig 3.
Presentation of the QSAR work flow chart for implemented in the present investigation.
Fig 4.
Presentation of Ramachandran Plot for pdbL6lu7, before and after optimization.
Fig 5.
Presentation of the Scattered plot (a) Graph of experimental vs. predicted pIC50 values for a model (b) Graph of residual vs. Predicted pIC50 values for a model (c) William’s plot for applicability domain of the developed QSAR model 1 (d) Insubria Plot for a QSAR model 1.
Fig 6.
Representation of the Scattered plot (a) Graph of experimental vs. Predicted pIC50 values for a model (b) Graph of Residual vs. Predicted pIC50 values for a model (c) Williams plot for the applicability domain of the model 2 (d) Insubria Plot for a QSAR model 2.
Table 1.
Presentation of the statistical parameters associated with fitting, double validation and Y-scrambling for QSAR model 1 and model 2.
Fig 7.
Skematic representation of the molecular descriptor fNH5B in molecules 3 and 9 only.
Fig 8.
Presentation of (A) 2D interaction of the Michael acceptor inhibitor N3 with Mpro, (B) Illustration of the molecular descriptor fNH5B in Michael acceptor inhibitor N3 (PDB ID: 2Q6F).
Fig 9.
Presentation and Mechanistic interpretation display of the molecular descriptor faroCC5B for the molecule 1 & 15 and 3 & 24.
Fig 10.
Presentation of Illustration of synchronous effect of molecular descriptors faroCC5B and fnotringOsp3C5B.
Fig 11.
Presentation of the molecular descriptor com_ringC_2A for the molecules 103 and 95(pink star in the molecule 103 and 95 indicate center of mass of the molecule).
Fig 12.
Presentation of (a) 2D interactions of compound 4 (ZINC ID: 32719065) with SARS-CoV-2 Mpro, (b) Comparison of docked conformation of pdb-6lu7 ligand (cyan colored) of SARS CoV2 Mpro and Hit compound-47 (zinc id-32719065) (orange colored).
Fig 13.
Presentation of Binding of the ligand, compound 4 (ZINC ID: 32719065) at the active pocket of SARS-CoV-2 Mpro showing extended conformation.
Table 2.
Presentation of Docking score (SARS Mpro) for the five most active hits identified in QSAR based virtual screening.
Fig 14.
Presentation of (A) 2D interactions of compound 4 (ZINC ID: 32719065) with MAO-B receptor, and (B) Comparison of docked conformation of pdb-2v61 ligand (Red colored) of MAO-B receptor and hit compound 4 (zinc id-32719065) (Ash colored).
Fig 15.
Depiction of i. MD simulation trajectory analysis of Root Mean Square Divisions (RMSD) of compound 4 (ZINC ID: 32719065) bound with SARS-CoV-2 Mpro (PDB ID: 6LU7) at 150 ns time frame in triplicate displayed: R1 (replicate 1) Root Mean Square Divisions (RMSD) plot of compound 4 (ZINC ID: 32719065) bound with SARS-CoV-2 Mpro (PDB ID: 6LU7) (red); R2 (replicate 2) Root Mean Square Divisions (RMSD) plot of compound 4 (ZINC ID: 32719065) bound with SARS-CoV-2 Mpro (PDB ID: 6LU7) (blue); R3 (replicate 3) Root Mean Square Divisions (RMSD) plot of compound 4 (ZINC ID: 32719065) bound with SARS-CoV-2 Mpro (PDB ID: 6LU7) (light green); ii. Portrayal of MD simulation trajectory analysis of Radius of gyration (Rg) of compound 4 (ZINC ID: 32719065) bound with SARS-CoV-2 Mpro (PDB ID: 6LU7) at 150 ns time frame in triplicate displayed: R1 (replicate 1) Radius of gyration (Rg) plot of compound 4 (ZINC ID: 32719065) bound with SARS-CoV-2 Mpro (PDB ID: 6LU7) (red); R2 (replicate 2) Radius of gyration (Rg) plot compound 4 (ZINC ID: 32719065) bound with SARS-CoV-2 Mpro (PDB ID: 6LU7) (blue); R3 (replicate 3) Radius of gyration (Rg) plot of compound 4 (ZINC ID: 32719065) bound with SARS-CoV-2 Mpro (PDB ID: 6LU7) (light green); iii. Representation of MD simulation trajectory analysis of Root Mean Square Fluctuations (RMSF) of compound 4 (ZINC ID: 32719065) bound with SARS-CoV-2 Mpro (PDB ID: 6LU7) at 150 ns time frame in triplicate displayed: R1 (replicate 1) Root Mean Square Fluctuations (RMSF) plot of compound 4 (ZINC ID: 32719065) bound with SARS-CoV-2 Mpro (PDB ID: 6LU7) (red); R2 (replicate 2) Root Mean Square Fluctuations (RMSF) plot of compound 4 (ZINC ID: 32719065) bound with SARS-CoV-2 Mpro (PDB ID: 6LU7) (blue); R3 (replicate 3) Root Mean Square Fluctuations (RMSF) plot of compound 4 (ZINC ID: 32719065) bound with SARS-CoV-2 Mpro (PDB ID: 6LU7) (light green); iv. Display of MD simulation trajectory analysis of Hydrogen Bonding (H-Bonds) of compound 4 (ZINC ID: 32719065) bound with SARS-CoV-2 Mpro (PDB ID: 6LU7) at 150 ns time frame in triplicate displayed: R1 (replicate 1) H-Bond plot of compound 4 (ZINC ID: 32719065) bound with SARS-CoV-2 Mpro (PDB ID: 6LU7) (red); R2 (replicate 2) H-Bond plot of compound 4 (ZINC ID: 32719065) bound with SARS-CoV-2 Mpro (PDB ID: 6LU7) (blue); R3 (replicate 3) H-Bond plot of compound 4 (ZINC ID: 32719065) bound with SARS-CoV-2 Mpro (PDB ID: 6LU7) (light green).
Table 3.
Depiction of Average values from the triplicates (R1, R2, and R3).
Fig 16.
Portrayal of [i] Potein-ligand contact histogram (H-bonds, Hydrophobic, Ionic, Water bridges) of the ligand, compound 4 (ZINC ID: 32719065) bound with SARS-CoV-2 Mpro recorded in a 150 ns simulation interval; [ii] Ligand atom interactions with the protein residues of 6LU7 bound with compound 47; [iii] Ligand torsion profile.
Fig 17.
Presentation of [i] Secondary Structure element distribution by residue index throughout the protein structure. Red indicates alpha helices, and blue indicate beta-strands of SARS-CoV-2 Mpro bound with compound 47; [ii] Protein-Ligand contraction with amino acid residues.
Fig 18.
Depiction of Stepwise trajectory analysis for every 25 ns displaying the protein and ligand conformation during 150 ns of simulation time scale.
Fig 19.
Presentation of Free Energy Landscape displaying the achievement of global minima (ΔG, kJ/mol) of Mpro in presence of compound 4 (ZINC ID: 32719065) with respect to their RMSD (nm) and Radius of gyration (Rg, nm).
Table 4.
Binding energy calculation of compound 4 (ZINC ID: 32719065) with SARS-CoV-2 Mpro and non-bonded interaction energies from MMGBSA trajectories.
Fig 20.
Portrayal of MMGBSA trajectory (0 ns, before simulation and 150 ns, after simulation) exhibited conformational changes of compound 4 (ZINC ID: 32719065) upon binding with the protein SARS-CoV-2 Mpro.
The arrows indicating the overall positional variation (movement and pose) of compound 4 (ZINC ID: 32719065) at the binding site cavity. Therefore, it can be suggested that the compound 4 (ZINC ID: 32719065) has good affinity for the major target SARS-CoV-2 Mpro.
Fig 21.