The inhibitory effect of some natural bioactive compounds against SARS-CoV-2 main protease: insights from molecular docking analysis and molecular dynamic simulation

Abstract

This work aimed at evaluating the inhibitory effect of ten natural bioactive compounds (1-10) as potential inhibitors of SARS-CoV-2-3CL main protease (PDB ID: 6LU7) and SARS-CoV main proteases (PDB IDs: 2GTB and 3TNT) by molecular docking analysis. The inhibitory effect of all studied compounds was studied with compared to some proposed antiviral drugs which currently used in COVID-19 treatment such as chloroquine, hydroxychloroquine, azithromycin, remdesivir, baloxvir, lopinavir, and favipiravir. Homology modeling and sequence alignment was computed to evaluate the similarity between the SARS-CoV-2-3CL main protease and other SARS-CoV receptors. ADMET properties of all studied compounds were computed and reported. Also, molecular dynamic (MD) simulation was performed on the compound which has the highest binding affinity inside 6LU7 obtained from molecular docking analysis to study it is stability inside receptor in explicit water solvent. Based on molecular docking analysis, we found that caulerpin has the highest binding affinity inside all studied receptors compared to other bioactive compounds and studied drugs. Our homology modeling and sequence alignment showed that SARS-CoV main protease (PDB ID: 3TNT) shares high similarity with 3CLpro (96.00%). Also, ADMET properties confirmed that caulerpin obeys Lipinski's rule and passes ADMET property, which make it a promising compound to act as a new safe natural drug against SARS-CoV-2-3CL main protease. Finally, MD simulation confirmed that the complex formed between caulerpin and 3CLpro is stable in water explicit and had no major effect on the flexibility of the protein throughout the simulations and provided a suitable basis for our study. Also, binding free energy between caulerpin and 6LU7 confirmed the efficacy of the caulerpin molecule against SARS-CoV-2 main protease. So, this study suggested that caulerpin could be used as a potential candidate in COVID-19 treatment.

Keywords: COVID-19 virus protease; MD simulation; caulerpin; molecular docking; natural products.

Figure 1.

All studied bioactive compounds under investigation in this work.

Figure 2.

The alignment sequence between SARS-CoV-2-3CLpro (PDB ID: 6LU7) and SARS sister (PDB ID: 3TNT). The α helices are shown as red blocks. The β sheets are shown as blue blocks.

Figure 3.

The final Sequence alignment model between SARS-CoV-2-3CLpro (PDB ID: 6LU7) and SARS sister (PDB ID: 3TNT).

Figure 4.

The Ramachandran plot of 6LU7.

Figure 5.

The best docking pose of the studied compounds generated using Pymol software. The SARS-CoV-2-3CLpro is shown in cartoon representation while the studied compounds are shown as red color surrounding by all sticks and byres of 6LU7 within 5 Å of compound.

Figure 6.

Docking analysis visualization of 6LU7 binding with all studied compounds generated using Pymol software. The yellow dots show H-bonds.

Figure 7.

MD snapdhot of solvated compound10-6LU7 system obtained at 30 nm.

Figure 8.

Plot of root mean square deviation (RMSD) of C–Cα–N backbone vs. simulation time for solvated 6LU7 in the absence and presence of compound 10 during 30 ns molecular dynamic simulations.

Figure 9.

The root mean square fluctuation (RMSF) values of 6LU7 in the absence and presence of compound 10 at 30 nm were plotted against residue numbers.

Figure 10.

Hydrogen bond profiles of 6LU7-Compound 10 complex at 30 nm.