Small Molecules to Destabilize the ACE2-RBD Complex: A Molecular Dynamics Study for Potential COVID-19 Therapeutics

Abstract

The ongoing COVID-19 pandemic has infected millions of people, claimed hundreds of thousands of lives, and made a worldwide health emergency. Understanding the SARS-CoV-2 mechanism of infection is crucial in the development of potential therapeutics and vaccines. The infection process is triggered by direct binding of the SARS-CoV-2 receptor-binding domain (RBD) to the host cell receptor, Angiotensin-converting enzyme 2 (ACE2). Many efforts have been made to design or repurpose therapeutics to deactivate RBD or ACE2 and prevent the initial binding. In addition to direct inhibition strategies, small chemical compounds might be able to interfere and destabilize the meta-stable, pre-fusion complex of ACE2-RBD. This approach can be employed to prevent the further progress of virus infection at its early stages. In this study, Molecular docking is employed to analyze the binding of two chemical compounds, SSAA09E2 and Nilotinib, with the druggable pocket of the ACE2-RBD complex. The structural changes as a result of the interference with the ACE2-RBD complex are analyzed by molecular dynamics simulations. Results show that both Nilotinib and SSAA09E2 can induce significant conformational changes in the ACE2-RBD complex, intervene with the hydrogen bonds, and influence the flexibility of proteins. Moreover, essential dynamics analysis suggests that the presence of small molecules can trigger large-scale conformational changes that may destabilize the ACE2-RBD complex.

Keywords: ACE2-RBD Complex; COVID-19; Docking; Molecular Dynamics; Nilotinib; SSAA09E2.

Figure 1:

(a) Electrostatic surface of ACE2-RBD complex and the pocket at the interface of ACE2 and RBD, Ligand-protein interactions for (b) Nilotinib, (c) SSAA09E2, and best docking poses of (d) Nilotinib, and (e) SSAA09E2.

Figure 2:

(a) RMSD of the ACE2 protein, (b) RMSF of the ACE2 protein, (c) RMSF of residues number 20–80 of the ACE2 protein, (d) snapshot of the ACE2 protein (blue), RBD (red) and interface residues number 20–80 (yellow)

Figure 3:

(a) RMSD of the RBD, (b) RMSF of the RBD, (c) Residues with more significant changes in the RMSF are shown with yellow sticks, Gly485 and Gln24 are shown by gray sticks (d) RMSD of ligand molecules

Figure 4:

R_g of the (a) ACE2, and (b) RBD proteins.

Figure 5:

Number of Hydrogen bonds for the (a) control ,(b) Nilotinib , and (c) SSAA09E2 and rolling average of hydrogen bonds for (d) Control, (e) Nilotinib, and (f) SSAA09E2.

Figure 6:

Eigenvectors and corresponding eigenvalues for various systems.

Figure 7:

Dynamic conformations projected onto the two first principal vectors for (a) control, (b) Nilotinib, (c) and SSAA09E2 cases. All cases are compared in part (d).

Figure 8:

Porcupine plots of characteristic dynamic fluctuations for the three lowest-frequency principal components