In silico evaluation of the compounds of the ayurvedic drug, AYUSH-64, for the action against the SARS-CoV-2 main protease

Thrigulla, Saketh Ram; Munikumar, Manne; Raju, Vankudavath Naik; Devaraj, P.; Boiroju, Naveen Kumar; Hemalatha, R.; Prasad, P V V; Gundeti, Manohar; Sisodia, Brijesh S.; Pawar, Sharad; Prasad, Goli Penchala; Chincholikar, Mukesh; Goel, Sumeet; Mangal, Anupam K; Gaidhani, Sudesh; Srikanth, Narayanam; Dhiman, Kartar Singh

doi:10.1016/j.jaim.2021.02.004

Cited by 45 publications

(35 citation statements)

References 51 publications

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“…In addition to these molecules, sterenin M was also reported in a recent computational study [39] to bind to the same active binding site as PF-07321332 and interact with the residues of catalytic dyad, but its total binding energy profile showed that the binding of PF-07321332 with protein was much stabler than the one of sterenin M [39]. In similar studies, the identified compounds bind to the same binding site, but the stability of complex is lower than the one of PF-07321332 [40,41]. Hence, considering the current pandemic situation, it is crucial to find some potent drug candidate with good binding affinity.…”

Section: Discussionmentioning

confidence: 57%

“…Therefore, 3CL pro is an attractive target for anti-COVID-19 drug discovery. In recent studies, many new compounds have been reported as potential inhibitors of 3CL pro [14,[39][40][41][42]. We included four of the potential inhibitors in our study, compared their binding energy and discussed their interactions with the protein to identify the potent inhibitor.…”

Section: Discussionmentioning

confidence: 99%

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Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations

Ahmad

Batool

Ain

et al. 2021

IJMS

102

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The novel coronavirus disease, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), rapidly spreading around the world, poses a major threat to the global public health. Herein, we demonstrated the binding mechanism of PF-07321332, α-ketoamide, lopinavir, and ritonavir to the coronavirus 3-chymotrypsin-like-protease (3CLpro) by means of docking and molecular dynamic (MD) simulations. The analysis of MD trajectories of 3CLpro with PF-07321332, α-ketoamide, lopinavir, and ritonavir revealed that 3CLpro–PF-07321332 and 3CLpro–α-ketoamide complexes remained stable compared with 3CLpro–ritonavir and 3CLpro–lopinavir. Investigating the dynamic behavior of ligand–protein interaction, ligands PF-07321332 and α-ketoamide showed stronger bonding via making interactions with catalytic dyad residues His41–Cys145 of 3CLpro. Lopinavir and ritonavir were unable to disrupt the catalytic dyad, as illustrated by increased bond length during the MD simulation. To decipher the ligand binding mode and affinity, ligand interactions with SARS-CoV-2 proteases and binding energy were calculated. The binding energy of the bespoke antiviral PF-07321332 clinical candidate was two times higher than that of α-ketoamide and three times than that of lopinavir and ritonavir. Our study elucidated in detail the binding mechanism of the potent PF-07321332 to 3CLpro along with the low potency of lopinavir and ritonavir due to weak binding affinity demonstrated by the binding energy data. This study will be helpful for the development and optimization of more specific compounds to combat coronavirus disease.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations

Ahmad

Batool

Ain

et al. 2021

IJMS

102

View full text Add to dashboard Cite

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“…Conversion of PDB to 6LU7 (PDBQT) done. 20,35 Analysis of In-silico interaction MGL tools Autodock 4.2. software approaches were used to predict the interaction energies between medicinal compounds and COVID-19 proteins. Interactions were analysed using the Lamarckian genetic approach (LGA).…”

Section: Mpro Molecule Preparationmentioning

confidence: 99%

Molecular Docking Studies on the Anti-viral Activity of Cellulose Acetate Phthalate (CAP) Against SARS-CoV-2 by Protease Mpro

Sharma

Guglani³

et al. 2021

Preprint

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Even after a year, the COVID-19 pandemic produced by the SARS-CoV-2 remains a major source of concerns for scientists. Surprisingly, the primary protease is a key target because of its role in viral propagation. As a result, no significant study in the field of adjuvant has been done too far. CAP stands for “Cellulose Acetate Phthalate”, an industrial polymer utilized in the enteric coating of tablets and capsules. CAP has been shown in certain trials to have anti-HIV properties by using the co-receptor location. Thus, CAP was tested against SAR-primary CoV-2's protease Mpro using in silico methods in the present study. Auto Dock was used to evaluate selected CAP molecules against SAR-CoV-2, and Discovery studio visualizer was used to create 3D and 2D interaction photos. CAP's binding energies were -3.05kcal/mol, -3.78kcal/mol, and -3.01kcal/mol during blind docking, site specific docking, and docking with a N3 inhibitor, respectively. Additionally, the discovery studio visualizer was utilized to look at interacting amino acids and 3D structures. Interestingly, the data from the discovery studio visualizer showed that it established H-bonds with Mpro residues, TYR37, TYR101, and LYS100 during blind docking and LYS88, TYR101, and LYS100 during site specific docking. The findings indicated that CAP binds non-competitively to co-receptor sites and that it may have synergistic effects with other medicines or medications. As a result, it's a good candidate for further testing in the lab and in the clinic.

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“…As per the in-silico study based on docking, it was found that 36 chemical compounds of the AYUSH 64 have good potential for anti SARS COV-2 activity. [20] It was also found to be effective in Influenza like Illness (ILI) in a clinical study. [21] It was worthwhile to explore the efficacy and safety of this formulation for COVID-19, considering its good efficacy in influenza like disease.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of Ayurveda Intervention (AYUSH 64) as add-on therapy for patients with COVID-19 infections – An open labelled, Parallel Group, Randomized controlled clinical trial

Bhardwaj

Godatwar²,

Charan

et al. 2021

Preprint

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COVID-19 pandemic impacted human health and the global economy. There is a huge uncertainty about the management of this disease, many drugs including some older drugs are being tested for efficacy and safety including the medicines from the complementary and alternative system. The Central Council for Research in Ayurvedic Sciences, India's apex body for Ayurvedic research and development under the Ministry of AYUSH, has developed a poly-herbal drug called AYUSH 64 for covid 19 which is considered to be having role in the COVID-19. This study was designed with the aim of assessing the efficacy and safety of AYUSH 64 in mild covid-19 patients as add on therapy with standard treatment. It was an open labelled, comparative, parallel group, Randomized controlled clinical trial. Total 60 stage I (mild) COVID 19 positive subjects were recruited, 30 were assigned to AYUSH 64 as an add on therapy along with the standard treatment and 30 were assigned to standard treatment as per the protocols. RT-PCR test was done as per government guidelines and protocol. Along with the RT-PCR clinical laboratory tests were also performed at screening as well as on the discharge as per the study schedule. Absolute events of negative RT-PCR at day 5 were more in the AYUSH 64 group as compared to control group but it was not statistically significant (70% Vs 54%, p=0.28). There was no significant difference between AYUSH 64 and control group for fever and respiratory symptoms or important lab parameters. No serious adverse event was reported from any group. AYUSH 64 has no significant beneficial effect as compared to control group, this may be because of the less sample size or no actual effect which need to be confirmed by studies with large sample size.

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In silico evaluation of the compounds of the ayurvedic drug, AYUSH-64, for the action against the SARS-CoV-2 main protease

Cited by 45 publications

References 51 publications

Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations

Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations

Molecular Docking Studies on the Anti-viral Activity of Cellulose Acetate Phthalate (CAP) Against SARS-CoV-2 by Protease Mpro

Efficacy and Safety of Ayurveda Intervention (AYUSH 64) as add-on therapy for patients with COVID-19 infections – An open labelled, Parallel Group, Randomized controlled clinical trial

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