In silico Screening of Potential SARS-CoV-2 Main Protease Inhibitors from Thymus schimperi

Figures & data

Table 1 Summary of Top Five Hits Screened Against SARS-CoV-2 M^pro

Ligand Name	Binding Affinity (kcal/Mol)			Visualization
	AV	MOE	Gold Score	Chimera	DS Studio		LigPlot
				Interacting Residues	Interacting Residues	H Bond	Interacting Residues	H Bond
Geranylisobutanoate	−4.8	−5.17	44.26	His41, Met49, Phe140, Leu141, Asn142, Gly143, Ser144, Cys145, His163, His164, Met165, Glu166, His172, Gln189	His41, Met49, Phe140, Leu141, Asn142, Gly143, Ser144, Cys145, His163, Met165, Glu166, Gln189	1: Glu166	His41, Met49, Leu141, Asn142, Ser144, Cys145, His163, Met165, Glu166, Gln189	2: Glu166, Ser144
Amphotericin-gamma	−5.5	−4.8	37.98	Thr25, Thr26, Leu27, His41, Met49, Phe140, Leu141, Asn142, Gly143, Ser144, Cys145, His163, His164, Met165, Glu166, His172	Leu, 27, His41, Met49, Phe140, Leu141, Asn142, Gly143, Ser144, Cys145, His163, His164, Met165, Glu166		His41, Phe140, Leu141, Asn142, Gly143, Ser144, Cys145, His163, His164, Met165, Glu166
Germacrene-D	−5.0	−4.6	35.78	Thr25, His41, Ser46, Met49, Phe140, Leu141, Asn142, Gly143, Ser144, Cys145, His163, His164, Met165, Glu166, His172, Arg188, Gln189	His41, Met49, Asn142, Gly143, Cys145, His163, Met165, Glu166, Gln189		His41, Met49, Asn142, Cys145, His163, Met165, Glu166, Gln189
3-Octane	−5.0	−5.17	44.88	His41, Met49, Phe140, Leu141, Asn142, Gly143, Ser144, Cys145, His163, His164, Met165, Glu166, His172, Gln189	His41, Met49, Phe140, Leu141, Asn142, Gly143, Ser144, Cys145, His163, His164, Met165, Glu166, His172, Gln189	1: Glu166	His41, Met49, Leu141, Asn142, Ser144, Cys145, His163, Met165, Glu166, Gln189	2: Glu166, Ser144
Vetivenene-beta	−5.6	−4.9	36.88	Glu55, Leu58, Ile59, Lys61, His80, Ser81, Met82	Glu55, Leu58, Ile59, His80, Ser81, Met82

Figure 1 3D and 2D representation of the best docked pose of the compound 3-octane highlighting the critical binding site residues of M^pro. (A) Ribbon representation of the ligand 3-octane bound to the M^pro. The blue color represents the ribbon representation of M^pro while the ligand is represented in green color. The protein residues interacting with the ligand are represented in orange color. (B) The surface representations of the M^pro depicting the ligand are tightly bound within the binding groove of the protein. (C) The 2D representation of the docked pose protein–ligand complex. (i) 2D interaction diagram of 3-octane–M^pro complex generated by MOE. (ii) Ligplot representation of the protein–ligand complex drawn by LigPlot+. (iii) 2D depiction of the docked complex highlighting hydrogen bonds and cation-p interaction through DS Visualizer.

Figure 2 Global stability analysis of ligand-hACE2 protein complexes throughout 200 ns all-atom MD simulation. (A) Analysis of RMSD trajectories for the 3-octane–M^pro protein complex throughout 200 ns MD simulation deciphering the primary conformational switches. (B) The radius of gyration for the protein–ligand complex reflects the complex structure’s global stability. (C) RMSF of protein–ligand complex depicting fluctuations across protein residues during 200 ns of MD simulations. (D) Extent of M^pro binding site coverage via SASA analysis along with the time evolution 200 ns all-atom MD simulation.

Figure 3 The structure superimposition of MD trajectories (0 ns, 50 ns, 100 ns, 150 ns, and 200 ns) over the pre-simulated 3-octane–M^pro complex. (A) The secondary structure representation of superimposed protein–ligand complexes. The ligand is represented in green color. (B) The surface representation of M^pro representing that ligand is bound within the same active site groove throughout the 200 ns of MD simulation run considering it stable active site conformation of the ligand.

Figure 4 Conformations of the 3-octane complex at M^pro binding site through selected trajectories.