Different compounds against Angiotensin-Converting Enzyme 2 (ACE2) receptor potentially containing the infectivity of SARS-CoV-2: an in silico study

Abstract

Novel SARS coronavirus or SARS-CoV-2 is a novel coronavirus that was identified and spread from Wuhan in 2019. On January 30th, the World Health Organization declared the coronavirus outbreak as a Global Public Health Emergency. Although Remdesivir and Molnupiravir are FDA-approved drugs for COVID-19, finding new efficient and low-cost antiviral drugs against COVID-19 for applying in more countries can still be helpful. One of the potential sources for finding new and low-cost drugs is the herbal compounds in addition to repurposing FDA-approved drugs. So, in this study, we focused on finding effective drug candidates against COVID-19 based on the computational approaches. As ACE2 serves as a critical receptor for cell entry of this virus. Inhibiting the binding site of SARS-CoV-2 on human ACE2 provides a promising therapeutic approach for developing drugs against SARS-CoV-2. Herein, we applied a bioinformatics approach to identify possible potential inhibitors of SARS-CoV-2. A library of FDA-approved compounds and five natural compounds was screened using Smina docking. Top-docking compounds are then applied in Molecular Dynamics (MD) simulation to assess the stability of ACE2-inhibitor complexes. Results indicate that Luteolin and Chrysin represent high conformation stability with ACE2 during 120 ns of Molecular Dynamics simulation. The binding free energies of Luteolin and Chrysin were calculated by the Molecular Mechanics/Poisson-Boltzmann Surface Area method (MM/PBSA) which confirmed the relative binding free energy of these drugs to ACE2 in favor of the effective binding. So, Luteolin and Chrysin could sufficiently interact with ACE2 and block the Spike binding pocket of ACE2 and can be a potential inhibitor against the binding of SARS-CoV-2 to ACE2 receptor which is an early stage of infection. Luteolin and Chrysin could be suggestive as beneficial compounds for preventing or reducing SARS-CoV-2 transmission and infection which need experimental work to prove.

Keywords: Angiotensin-converting enzyme 2; Chrysin; Luteolin; Molecular Docking Simulation; Molecular Dynamics simulation; SARS-CoV-2; Spike protein.

Fig. 1

Schematic view of the whole strategy in this study

Fig. 2

Human ACE2 sequence. Amino acids of ACE2 which interact with the Spike protein of SARS-CoV and SARS-CoV-2 are shown with asterisks. Amino acids which play a role in interaction with ACE2 in SARS-CoVs are Ser19(S), Gln24(Q), Thr27(T), Phe28(F), Asp30(D), Lys31(K), His34(H), Glu37(E), Asp38(D), Tyr 41(Y), Gln42(Q), Leu45(L), Leu79(L), Met82(M), Tyr83(Y), Gln325(Q), Gly326(G), Glu329(E), Asn330(N), Lys353(K), Gly354(G), Asp355(D), and Arg357(R)

Fig. 3

Docking result of the candidate drugs against the SAR-CoV-2 binding site on ACE2. Results indicate that all candidate drugs could interact effectively with the ACE2. The minimized affinity of Smina docking results in Luteolin, Chrysin, Pimozide, and Ursodeoxycholic acids is −7.7, −7.1, −8.5, and −8.7, respectively

Fig. 4

Molecular Dynamics simulation analysis of Luteolin and Chrysin throughout the interaction with ACE2 receptor during 120 ns of the simulation. A RMSD plots represent that Luteolin-ACE2 and Chrysin-ACE2 reach a steady-state during 120 ns of simulation with the RMSD around 0.7 nm. Free ACE2 is defined as the receptor in the RMSD plot. B RMSD plots of Luteolin and Chrysin during 120 ns of simulation. C Rg plot indicates that Luteolin-ACE2 and Chrysin-ACE2 have the Rg values of around 2.1 which is less than the Rg value of 2.4 for the free form of ACE2 (defined as the receptor in the plot). D SASA plot presents that Luteolin-ACE2 and Chrysin-ACE2 have similar SASA values which are less than the free form of the ACE2. E Hydrogen bond plot figures out that Luteolin-ACE2 has a higher number of hydrogen bonds than Chrysin. F RMSF plot demonstrating that Luteolin has higher RMSF fluctuation than Chrysin and the free form of ACE2 (defined as the receptor in the plot)

Fig. 5

Secondary structure analysis plot during 120 ns of the simulation. A The free form of the ACE2. B Luteolin-ACE2 complex. C Chrysin-ACE2 complex. D Pimozide-ACE2 complex. E Ursodeoxycholic acid-ACE2 complex. Data showed all compounds caused no changes in the ACE2 structure during the simulation and no drastic change in the secondary structure was observed during the simulation except for Pimozide which increases the alpha-helix structure around 200-250 region compared to free ACE2. Luteolin and Chrysin caused more stable structures

Fig. 6

Molecular Dynamics simulation analysis of Luteolin and Chrysin throughout the interaction with the Spike protein during 120 ns of the simulation. A RMSD plots represent that Luteolin-Spike reaches a steady-state during 90 ns with RMSD value around 0.2 nm, Chrysin-Spike reaches a steady-state during 80 ns of simulation with RMSD around 0.4 nm. B RMSD plots of Luteolin and Chrysin during 120 ns of simulation. C Rg plot indicates that Luteolin-Spike and Chrysin-Spike have an Rg value of around 1.8 which is less than the Rg value of Luteolin-Spike and free Spike. D SASA plot presents that Luteolin-Spike and Chrysin-Spike have less SASA values than the free Spike. E Hydrogen bond plots figure out that Luteolin-Spike has a higher number of hydrogen bonds than Chrysin. F RMSF plot demonstrating that Chrysin has higher RMSF fluctuation than Luteolin and free Spike, especially in regions 440-440 and 495-505

Fig. 7

Molecular dynamics simulation of Pimozide and Ursodeoxycholic acid throughout the interaction with the ACE2 receptor during 120 ns of the simulation. A RMSD plot of Pimozide and Ursodeoxycholic acid shows that both drugs have the same RMSD value to the free form of ACE2. Besides, both drugs represent a slight fluctuation around 100 ns of the simulation. B RMSD plot of Pimozide and Ursodeoxycholic acid during simulation. Data shows that Ursodeoxycholic acid has less RMSD value than Pimozide. C Rg plot of Pimozide and Ursodeoxycholic acid showing lower Rg value than the free form of ACE2 which indicates both drugs caused a more relax and compact structure compared to the free form of ACE2. D SASA plot of Pimozide and Ursodeoxycholic acid illustrates that both drugs make surface structure changes in ACE2 compared to the free form of ACE2. E Hydrogen bond plot of Pimozide and Ursodeoxycholic acid shows that both drugs have the same hydrogen bond. F RMSF plot of Pimozide and Ursodeoxycholic acid indicates that Ursodeoxycholic acid has more fluctuation than Pimozide and the free form of ACE2. Also, Pimozide shows the same fluctuation compared to the free form of ACE2

Fig. 8

Molecular Dynamics simulation analysis of Pimozide and Ursodeoxycholic acid throughout the interaction with the Spike protein during 120 ns of simulation. A RMSD plots represent that the Pimozide-Spike and Ursodeoxycholic acid-Spike complexes have higher RMSD values than the free form of the Spike. B RMSD plots of Pimozide and Ursodeoxycholic acid during 120 ns of the simulation. Data show that Ursodeoxycholic acid has lower fluctuation with an RMSD value of 0.1 nm than Pimozide. C Rg plot indicates that Pimozide-Spike and Ursodeoxycholic acid-Spike have an Rg value less than the free form of the Spike. D SASA plot presents that Ursodeoxycholic acid-Spike and Pimozide-Spike have lower SASA values than the free form of the spike. E Hydrogen bond plot figures out that Ursodeoxycholic acid has a higher number of hydrogen bonds than Pimozide. F RMSF plot demonstrates that Ursodeoxycholic acid and Pimozide have higher RMSF fluctuation than the free form of the Spike

Fig. 9

Tertiary structure analysis of drug candidates—ACE2 after MD simulation. A Tertiary structure of the free form of the ACE2. The binding site of ACE2 is depicted within the circle. B The tertiary structure of the Luteolin in complex with the ACE2. C Tertiary structure of the Chrysin in the complex with ACE2. D The tertiary structure of Ursodeoxycholic acid in complex with ACE2. E The tertiary structure of Pimozide in complex with ACE2. As shown, Luteolin and Chrysin drug candidates interact with the ACE2 binding pocket. Also, Ursodeoxycholic acid and Pimozide drug candidates still interact with the ACE2 binding pocket. The structures were created by PyMoL software

Fig. 10

Binding free energy of critical amino acids in ACE2 binding site computed with MMPBSA. A Luteolin and Chrysin. B Pimozide and Ursodeoxycholic acid; result indicates that Ursodeoxycholic acid has near-zero binding free energy value compared to Pimozide