Molecular Docking and Dynamics Simulation Revealed the Potential Inhibitory Activity of ACEIs Against SARS-CoV-2 Targeting the h ACE2 Receptor

Abstract

The rapid and global spread of a new human coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has produced an immediate urgency to discover promising targets for the treatment of COVID-19. Here, we consider drug repurposing as an attractive approach that can facilitate the drug discovery process by repurposing existing pharmaceuticals to treat illnesses other than their primary indications. We review current information concerning the global health issue of COVID-19 including promising approved drugs, e.g., human angiotensin-converting enzyme inhibitors (hACEIs). Besides, we describe computational approaches to be used in drug repurposing and highlight examples of in-silico studies of drug development efforts against SARS-CoV-2. Alacepril and lisinopril were found to interact with human angiotensin-converting enzyme 2 (hACE2), the host entranceway for SARS-CoV-2 spike protein, through exhibiting the most acceptable rmsd_refine values and the best binding affinity through forming a strong hydrogen bond with Asn90, which is assumed to be essential for the activity, as well as significant extra interactions with other receptor-binding residues. Furthermore, molecular dynamics (MD) simulations followed by calculation of the binding free energy were also carried out for the most promising two ligand-pocket complexes from docking studies (alacepril and lisinopril) to clarify some information on their thermodynamic and dynamic properties and confirm the docking results as well. These results we obtained probably provided an excellent lead candidate for the development of therapeutic drugs against COVID-19. Eventually, animal experiments and accurate clinical trials are needed to confirm the potential preventive and treatment effect of these compounds.

Keywords: ACEIs; COVID-19; hACE2; molecular docking; molecular dynamics.

Figure 1

Chemical structures of the tested ACEIs.

Figure 2

Schematic representation showing the idea of repurposing the FDA-approved ACEIs as COVID-19 entrance inhibitors through the inhibition of the hrsACE2 receptor.

Figure 3

(A) High-resolution crystal structures of coronavirus target explain the native ligand (NAG) in the active pocket (PDB ID: 6VW1, Score = −4.4, RMSD = 1.3). (B) High-resolution crystal structures of coronavirus target explain Alacepril in the active pocket (PDB ID: 6VW1, Score = −5.1, RMSD = 1.3). (C) High-resolution crystal structures of coronavirus target explain Lisinopril in the active pocket (PDB ID: 6VW1, Score = −4.6, RMSD = 1.3). N.B: The surface and maps representations show the H-bond donor, H-bond acceptor, and hydrophobic regions around the docked compound.

Figure 4

Analysis of RMSD trajectories for the ligand-hACE2 protein complexes throughout 100 ns all-atom MD simulation. (A) Complex RMSD; (B) ligand RMSD; (C) protein RMSD; (D) binding pocket residues RMSD, relative to backbone vs. MD simulation time in nanoseconds. Alacepril/hACE2 and lisinopril/hACE2 complexes as well as glycosylated (NAG)-bound and apo-state (all glycans being removed) hACE2 proteins are illustrated in pink, blue, green, and yellow colors, respectively.

Figure 5

Global stability analysis of ligand-hACE2 protein complexes throughout 100 ns all-atom MD simulation. (A) Complex Rg; (B) protein Rg, vs. MD simulation time in nanoseconds. Alacepril/hACE2 and lisinopril/hACE2 complexes as well as glycosylated (NAG)-bound and apo-state (all glycans being removed) hACE2 proteins are illustrated in pink, blue, green, and yellow colors, respectively.

Figure 6

Relative ΔRMSF analysis of ligand-hACE2 protein complexes throughout 100 ns all-atom MD simulation. Protein backbone ΔRMSF trajectories were determined from the independent MD-simulated hACE2 apo-state against the complexed protein with alacepril, lisinopril, or NAG, which were shown as a function of residue number 19-to-619. Alacepril/hACE2, lisinopril/hACE2, and glycosylated (NAG)/hACE2 complexes are illustrated in red, blue, and green colors, respectively.

Figure 7

Conformations of the ligand-protein complex at hACE2 binding site through selected trajectories. (A) Alacepril; (B) lisinopril; (C) NAG. Protein is represented in green, yellow, and red cartoon 3D-representation corresponding to initial (0 ns), dynamic equilibrium (70 ns), and last (100 ns) extracted trajectories, respectively. The key binding residues (lines), ligands (sticks), and hydrophilic interactions (hydrogen bonding; dashed lines) are all presented in colors corresponding to their respective extracted trajectory.

Figure 8

Extent of hACE2 binding site coverage via SASA analysis along with the time evolution 100 ns all-atom MD simulation. Surface occlusion is defined as the surface percentage being covered via NAG being calculated relying on the SASA differences for the binding site surface in the presence and absence of NAG glycans. Three different probe sizes (1.4, 7.2, and 10 Å) were utilized for calculating the SASA values. Data are represented as % surface occlusion vs. the MD simulation time in nanoseconds.

Figure 9

Time-evolution of hydrogen bond distances for alacepril with hACE2 key binding residues vs. 100-ns MD simulation time. (A) Asn90 and Gln96; (B) Asp30 and Thr92. The Y- and X-axes correlate to the apparent hydrogen bond (Donor-H…. Acceptor) distance in Å and MD simulation time in nanoseconds, respectively.

Figure 10

Binding-free energy/residue decomposition illustrating the protein residue contribution at alacepril-hACE2 protein complex ΔG_binding calculation. The residue-wise energy contributions across (A) 30–70 ns and (B) 80–100 ns MD simulation timeframes were represented in blue, brown, and green colored bars for alacepril, lisinopril, and NAG, respectively. Lower panels are expanded versions of three designated residue regions (19–115, 300–400, and 500–614) of the upper panels.