Truncated human angiotensin converting enzyme 2; a potential inhibitor of SARS-CoV-2 spike glycoprotein and potent COVID-19 therapeutic agent

Abstract

The current pandemic of Covid-19 caused by SARS-CoV-2 is continued to spread globally and no potential drug or vaccine against it is available. Spike (S) glycoprotein is the structural protein of SARS-CoV-2 located on the envelope surface, involve in interaction with angiotensin converting enzyme 2 (ACE2), a cell surface receptor, followed by entry into the host cell. Thereby, blocking the S glycoprotein through potential inhibitor may interfere its interaction with ACE2 and impede its entry into the host cell. Here, we present a truncated version of human ACE2 (tACE2), comprising the N terminus region of the intact ACE2 from amino acid position 21-119, involved in binding with receptor binding domain (RBD) of SARS-CoV-2. We analyzed the in-silico potential of tACE2 to compete with intact ACE2 for binding with RBD. The protein-protein docking and molecular dynamic simulation showed that tACE2 has higher binding affinity for RBD and form more stabilized complex with RBD than the intact ACE2. Furthermore, prediction of tACE2 soluble expression in E. coli makes it a suitable candidate to be targeted for Covid-19 therapeutics. This is the first MD simulation based findings to provide a high affinity protein inhibitor for SARS-CoV-2 S glycoprotein, an important target for drug designing against this unprecedented challenge.Communicated by Ramaswamy H. Sarma.

Keywords: ACE2; MD simulation; SARS-CoV-2; inhibitor; protein-protein docking; spike glycoprotein.

Figure 1.

Structural analysis of the (A) intact human ACE2 (pink) recognition by RBD (blue) of SARS-CoV-2 S protein. The binding interface of ACE2 comprising two α-helices is shown in red color. (B) ACE2-RBD binding interface showing residues of ACE2 (red) involved in interaction with RBD (blue). (C) tACE2-RBD complex. (D) Binding residues of tACE2 (red) showing interaction with RBD (blue). The interactions are denoted by black dots. (D) Surface model of ACE2-RBD complex showing interaction of intact ACE2 (pink), binding interface of ACE2 (red) and RBD (blue) and (E) surface model of tACE2-RBD complex showing tACE2(red) and RBD (blue).

Figure 2.

RMSD plot of the ACE2-RBD (red) and tACE2-RBD complex (violet) backbone atoms. The tACE2 complex showing less RMSD value than the intact ACE2, indicating its higher complex stability than the intact ACE2.

Figure 3.

RMS fluctuation of residues side chains of (A) tACE2, (B) RBD in complex with tACE2, (C) Intact ACE2 and (D) RBD in complex with ACE2.

Figure 4.

PDB trajectories of the intact ACE2-RBD (A&B) and tACE2-RBD complex (C&D), showing the backbone fluctuation of protein structure after a 20 ns MD simulation run. A slight fluctuation can be seen in the RBD of the tACE2 complex at position 471–489, highlighted yellow. ACE2 variants and RBD are shown by red and blue colors, respectively.

Figure 5.

Radius of gyration (Rg) plot of ACE2-RBD (red) and tACE2-RBD complex (violet).

Figure 6.

Solubility prediction profile score of (A) intact ACE2 showing most of the residues in the window are below 0 (cyan) and −1 (red), while very few residues are above 1 (blue), favors insoluble expression for intact ACE2. (B) a large number of residues are between −1 and 1 (cyan), while a window of 7 residues at C-terminal are above 1 (blue), favoring total solubility score above 0, hence soluble expression for tACE2.