Enfuvirtide, an HIV-1 fusion inhibitor peptide, can act as a potent SARS-CoV-2 fusion inhibitor: an in silico drug repurposing study

Abstract

Regarding the urgency of therapeutic measures for coronavirus disease 2019 (COVID-19) pandemic, the use of available drugs with FDA approval is preferred because of the less time and cost required for their development. In silico drug repurposing is an accurate way to speed up the screening of the existing FDA-approved drugs to find a therapeutic option for COVID-19. The similarity in SARS-CoV-2 and HIV-1 fusion mechanism to host cells can be a key point for Inhibit SARS-CoV-2 entry into host cells by HIV fusion inhibitors. Accordingly, in this study, an HIV-1 fusion inhibitor called Enfuvirtide (Enf) was selected. The affinity and essential residues involving in the Enf binding to the S2 protein of SARS-CoV-2, HIV-1 gp41 protein and angiotensin-converting enzyme 2 (ACE-2) as a negative control, was evaluated using molecular docking. Eventually, Enf-S2 and Enf-gp41 protein complexes were simulated by molecular dynamics (MD) in terms of binding affinity and stability. Based on the most important criteria such as docking score, cluster size, energy and dissociation constant, the strongest interaction was observed between Enf with the S2 protein. In addition, MD results confirmed that Enf-S2 protein interaction was remarkably stable and caused the S2 protein residues to undergo the fewest fluctuations. In conclusion, it can be stated that Enf can act as a strong SARS-CoV-2 fusion inhibitor and demonstrates the potential to enter the clinical trial phase of COVID-19. Communicated by Ramaswamy H. Sarma.

Keywords: COVID-19; Enfuvirtide; SARS-CoV-2; in silico drug repurposing; molecular docking; molecular dynamics.

Figure 1.

The multiple sequence alignments of the HR1 and HR2 domains of S2 and gp41 proteins using CLC Workbench. The conserved residues between the binding site of S2 and gp41 proteins are marked in red highlight.

Figure 2.

(A) The molecular docking of Enf-S2 protein complex. In the close-up view, the residues involved in the binding site of the S2 protein are demonstrated in yellow while the residues essential for HR1-HR2 interaction are shown in blue. (B) The molecular docking of Enf-gp41 protein complex. The binding site of gp41 protein is presented in yellow. (C) The molecular docking of Enf-ACE2 receptor complex. The binding site of the ACE2 receptor is indicated in yellow. In all parts, the S2, gp41 and ACE2 proteins are shown in green while Enf is shown in red.

Figure 3.

The root mean square deviation (RMSD) values of Cα of the S2 protein-Enf complex and the S2 protein alone.

Figure 4.

The RMSF fluctuation values of the S2 protein-Enf complex and the S2 protein alone.

Figure 5.

The SASA values of the S2 protein-Enf complex and the S2 protein alone.

Figure 6.

(A) The number of H-bonds between S2 protein and Enf. (B) Analysis of the electrostatic and (C) van der Waals energies.

Figure 7.

The binding free energy profile of the S2/gp41 proteins dissociated from the S2 protein-Enf and the gp41-Enf complexes.

Figure 8.

The interactions of the S2 protein and Enf created by Pymol software. (A) The cartoon 3D image of S2 protein-Enf complex. (B) The surface structure of S2 protein-Enf complex. The 3D images indicated that Enf binds tightly to the S2 protein and can fill the cavities, as proved by the binding energies. The S2 protein and Enf are shown in green and red, respectively.