The recent outbreak of the coronavirus disease COVID-19 is putting the world towards a great threat. A recent study revealed COVID-19 main protease (M pro) is responsible for the proteolytic mutation of this virus and is essential for its life cycle. Thus inhibition of this protease will eventually lead to the destruction of this virus. In-Silico Molecular docking was performed with the Native ligand and the 15 flavonoid based phytochemicals of Calendula officinals to check their binding affinity towards the COVID-19 main protease. Finally, the top 3 compounds with the highest affinity have been chosen for molecular dynamics simulation to analyses their dynamic properties and conformational flexibility or stability. In-Silico Docking showed that major phytochemicals of Calendula officinals i.e. rutin, isorhamnetin-3-O-b-D, calendoflaside, narcissin, calendulaglycoside B, calenduloside, calendoflavoside have better binding energy than the native ligand (inhibitor N3). MD simulation of 100 ns revealed that all the protease-ligand docked complexes are overall stable as compare to M pro-native ligand (inhibitor N3) complex. Overall, rutin and caledoflaside showed better stability, compactness, and flexibility. Our in silico (Virtual molecular docking and Molecular dynamics simulation) studies pointed out that flavonoid based phytochemicals of calendula (rutin, isorhamnetin-3-O-b-D, calendoflaside) may be highly effective for inhibiting M pro which is the main protease for SARS-CoV-2 causing the deadly disease COVID-19. Rutin is already used as a drug and the other two compounds can be made available for future use. Thus the study points a way to combat COVID-19 by the use of major flavonoid based phytochemicals of Calendula officinals.
A new strain of coronavirus (CoV) has been identified as SARS-CoV-2, which is responsible for the recent COVID-19 pandemic. Currently, there is no approved vaccine or drug available to combat the pandemic. COVID-19 main protease (M pro) is a key CoV enzyme, which plays an important role in triggering viral replication and transcription, turns it into an attractive target. Therefore, we aim to screen natural products library to find out potential COVID-19 M pro inhibitors. Plant-based natural compounds from Sigma-Aldrich plant profiler chemical library have been screened through virtual molecular docking and molecular dynamics simulation to identify potential inhibitors of COVID M pro. Our virtual molecular docking results have shown that there are twenty-eight natural compounds with a greater binding affinity toward the COVID-19 M pro inhibition site as compared to the co-crystal native ligand Inhibitor N3 (-7.9 kcal/mol). Also, molecular dynamics simulation results have confirmed that Peonidin 3-O-glucoside, Kaempferol 3-Ob-rutinoside, 4-(3,4-Dihydroxyphenyl)-7-methoxy-5-[(6-O-b-D-xylopyranosyl-b-D-glucopyranosyl)oxy]-2H-1benzopyran-2-one, Quercetin-3-D-xyloside, and Quercetin 3-O-a-L-arabinopyranoside (selected based on the docking score) possess a significant amount of dynamic properties such as stability, flexibility and binding energy. Our In silco results suggests that all the above mention natural compounds have the potential to be developed as a COVID-19 M pro inhibitor. But before that, it must go through under the proper preclinical and clinical trials for further scientific validation.
<p>SARS-CoV-2 uses RBD of Spike (S) protein to attach with human cell via ACE2
receptor, followed by protease priming at S1/S2 site resulted in host cell
entry and pathogenesis. In this context, we focused our aim in studying natural
mutations harboring in Spike protein of SARS-CoV-2. We have analyzed 420
COVID-19 cases. G476S and V483G mutation are observed which lies in the RBD
region where as the prevalent D614G mutation is observed in the vicinity of
S1/S2 site. Interestingly MD simulation supports strong favorable interaction
of ACE2 with RBD region containing V483A mutation as compared to G476S and
reference wild Wuhan S protein. Radius of gyration analysis also showed high degree of
compactness in V483A. The
landscape plot and Gibbs free energy also support our findings. Overall, our
study indicates that V483G in
the RBD region can enhance its binding with the human ACE2 receptor. Interestingly
D614G mutation in vicinity of S1/S2 region introduced a new cleavage site specific
for a serine protease elastase that is anticipated to broaden the virus host
cell tropism. Hence, both V483A and D614G mutations led to enhanced and broaden
the virus host cell entry and transmission of the disease. Further epitope
mapping analysis revealed G476S and D614G mutations as antigenic determinants
and thus these mutations are important while designing a therapeutics vaccine
or chimeric antibody. This
finding will help in further understanding the role of such arising mutations
in modulating immunogenicity, viral tropism and pathogenesis of the disease, which
in lieu will help in designing vaccine more precisely to mitigate pandemic COVID-19.
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