Dieckol and Its Derivatives as Potential Inhibitors of SARS-CoV-2 Spike Protein (UK Strain: VUI 202012/01): A Computational Study

Abstract

The high risk of morbidity and mortality associated with SARS-CoV-2 has accelerated the development of many potential vaccines. However, these vaccines are designed against SARS-CoV-2 isolated in Wuhan, China, and thereby may not be effective against other SARS-CoV-2 variants such as the United Kingdom variant (VUI-202012/01). The UK SARS-CoV-2 variant possesses D614G mutation in the Spike protein, which impart it a high rate of infection. Therefore, newer strategies are warranted to design novel vaccines and drug candidates specifically designed against the mutated forms of SARS-CoV-2. One such strategy is to target ACE2 (angiotensin-converting enzyme2)-Spike protein RBD (receptor binding domain) interaction. Here, we generated a homology model of Spike protein RBD of SARS-CoV-2 UK strain and screened a marine seaweed database employing different computational approaches. On the basis of high-throughput virtual screening, standard precision, and extra precision molecular docking, we identified BE011 (Dieckol) as the most potent compounds against RBD. However, Dieckol did not display drug-like properties, and thus different derivatives of it were generated in silico and evaluated for binding potential and drug-like properties. One Dieckol derivative (DK07) displayed good binding affinity for RBD along with acceptable physicochemical, pharmacokinetic, drug-likeness, and ADMET properties. Analysis of the RBD-DK07 interaction suggested the formation of hydrogen bonds, electrostatic interactions, and hydrophobic interactions with key residues mediating the ACE2-RBD interaction. Molecular dynamics simulation confirmed the stability of the RBD-DK07 complex. Free energy calculations suggested the primary role of electrostatic and Van der Waals' interaction in stabilizing the RBD-DK07 complex. Thus, DK07 may be developed as a potential inhibitor of the RBD-ACE2 interaction. However, these results warrant further validation by in vitro and in vivo studies.

Keywords: COVID-19; marine-derived compounds; molecular docking and simulation; natural compounds; seaweeds; spike protein.

Figure 1

Homology modeling and validation of RBD from the Spike protein of UK SARS-CoV-2 strain. (A) Sequence alignment of target with the template (PDB ID: 6ZBP). The mutated residues (Y453F and N501Y) are highlighted in the red box, (B) QMEAN4 score of the generated model, as compared to the non-redundant set of PDB structures, (C) Ramachandran plot of the generated model, and (D) Superimposition of the generated model (blue color) on to the three-dimensional structure of the template (red color).

Figure 2

Molecular docking between DK07 and RBD of SARS-CoV-2 Spike protein in extra-precision (XP) mode. (A) 2D representation of Dieckol derivative DK07; (A,B) 2D representation showing binding of DK07 to the groove of RBD where ACE2 binds; (C) 3D representation showing binding of DK07 at the binding pocket of RBD; and (D) interaction between DK07 and RBD of Spike protein, showing the involvement of different amino acid residues and the molecular forces.

Figure 3

Molecular dynamics (MD) simulation of RBD–DK07 complex. (A) RMSD (root mean square deviation) of RBD alone (teal color) and in the presence of DK07 (brown color); (B) RMSF (root mean square fluctuation) of RBD in the presence of DK07 (red color), as compared with B-factor, which was determined during X-ray crystallography (teal color).

Figure 4

Interaction between RBD and DK07 during simulation. (A) Percentage of RBD–DK07 secondary structure element (SSE) varied during simulation, (B) the number of contacts between RBD and DK07 as a function of simulation, (C) participation of different amino acid residues of RBD in making contacts with DK07 as a function of simulation.

Figure 5

Variation in (A) rGyr (radius of gyration), (B) MSA (molecular surface area), (C) SASA (solvent accessible surface area), and (D) PSA (polar surface area) of RBD–DK07 complex during MD simulation.