Identification of Papain-Like Protease inhibitors of SARS CoV-2 through HTVS, Molecular docking, MMGBSA and Molecular dynamics approach

Coronaviruses (CoVs) are a large group of enveloped positive sense single-stranded RNA viruses that can cause disease to humans. These are zoonotic having potential to cause large-scale outbreaks of infections widely causing morbidity and mortality. Papain-Like Proteases (PLpro) is a cysteine protease, essential for viral replication and proliferation, as a highly conserved enzyme it cleaves peptide linkage between Nsp1, Nsp2, Nsp3, and Nsp4. As a valid therapeutic targets it stops viral reproduction and boosts host immune response thereby halting further spread of infection. In the purpose of identifying inhibitors targeting Papain-Like Proteases (PLpro) we initiated a high throughput virtual screening (HTVS) protocol using a SuperNatural Database. The XP docking results revealed that two compounds SN00334175 and SN00162745 exhibited docking score of -10.58 kcal/mol and -9.93 kcal/mol respectively. The Further PRIME MMGB-SA studies revealed Van der Waal energy and hydrophobic energy terms as major contributors for total binding free energy. The 100 ns molecular dynamics simulation of SN00334175/7JN2 and SN00162745/7JN2 revealed that these complexes were stabilized with ligand binding forming interactions with Gly266, Asn267, Tyr268, Tyr273, Thr301 and Asp302, Lys157, Leu162, Asp164, Arg166, Glu167, Pro248, Tyr264.

Revisiting the South Indian Traditional Plants against Several Targets of SARS-CoV-2 - An in silico Approach.

BACKGROUND: The south Indian Telugu states will celebrate a new year called 'Ugadi' which is a south Indian traditional festival. The ingredients used in ugadi pachadi have often also been used in food as well as traditional Ayurveda and Siddha medicinal preparations. Coronaviruses (CoVs) are a diverse family of enveloped positive-sense single-stranded RNA viruses which can infect humans and have the potential to cause large-scale outbreaks. OBJECTIVE: Considering the benefits of ugadi pachadi, we investigated the binding modes of various phytochemical constituents reported from its ingredients against five targets of SARS-CoV-2. METHODS: Flexible-ligand docking simulations were achieved through AutoDock version 1.5.6. Following 50ns of molecular dynamics simulation using GROMACS 2018.1 software and binding free energy (ΔGbind) of the protein-ligand complexes were calculated using the g_mmpbsa tool. ADME prediction was done using Qikprop of Schrodinger. RESULTS: From the molecular docking and MM/PBSA results compound Eriodictin exhibited the highest binding energy when complexed with nucleocapsid N protein (6M3M) (-6.8 kcal/mol, - 82.46 kJ/mol), bound SARS-CoV-2-hACE2 complex (6M0J) (-7.4 kcal/mol, -71.10 kJ/mol) and Mpro (6XR3) (-8.6 kcal/mol, -140.21 kJ/mol). Van der Waal and electrostatic energy terms highly favored total free energy binding. CONCLUSION: The compounds Eriodictin, Vitexin, Cycloart-3, 24, 27-triol, Agigenin, Mangiferin, Mangiferolic acid, Schaftoside, 27-Hydroxymangiferonic acid, Quercetin, Azadirachtol, Cubebin, Isomangiferin, Isoquercitrin, Malicarpin, Orientin and procyanidin dimer exhibited satisfactory binding energy values when compared with standard molecules. The further iterative optimization of high-ranked compounds following validation by in vitro and in vivo techniques assists in discovering therapeutic anti-SARS-CoV-2 molecules.

Activity of phytochemical constituents of Curcuma longa (turmeric) and Andrographis paniculata against coronavirus (COVID-19): an in silico approach.

BACKGROUND: In early 2020, many scientists are rushing to discover novel drugs and vaccines against the coronavirus, and treatments for COVID-19, because coronavirus disease 2019 (COVID-19), a life-threatening viral disease, affected first in China and quickly spread throughout the world. In this article, in silico studies have been performed to explore the binding modes of chemical constituents for natural remedies like Curcuma longa (turmeric) and Andrographis paniculata against COVID-19 (PDB ID 5R82) targeting coronavirus using Schrodinger suit 2019-4. The molecular docking studies are performed by the Glide module, in silico ADMET screening was performed by the QikProp module, and binding energy of ligands was calculated using the Prime MM-GB/SA module. RESULTS: The chemical constituents from turmeric like cyclocurcumin and curcumin and from Andrographis paniculata like andrographolide and dihydroxy dimethoxy flavone are significantly binding with the active site of SARS CoV-2 main protease with Glide score more than - 6 when compared to the currently used drugs hydroxychloroquine (- 5.47) and nelfinavir (- 5.93). When compared to remdesivir (- 6.38), cyclocurcumin from turmeric is significantly more active. The docking results of the compounds exhibited similar mode of interactions with SARS CoV-2. Main protease and the residues THR24, THR25, THR26, LEU27, SER46, MET49, HIE41, GLN189, ARG188, ASP187, MET165, HIE164, PHE181, and THR54 play a crucial role in binding with ligands. CONCLUSION: Based on in silico investigations, the chemical constituents from turmeric like cyclocurcumin and curcumin and from Andrographis paniculata like andrographolide and dihydroxy dimethoxy flavone, significantly binding with the active site of SARS CoV-2 main protease, may produce significant activity and be useful for further development.

Role of natural products towards the SARS-CoV-2: A critical review.

Despite the fact that various therapeutic compounds are being investigated, there is still a scarcity of effective and reliable therapeutic regimens to treat COVID-19. Ever since the COVID-19 pandemic, a diversity of traditional herbal treatments has been investigated to cure infected people, either alone or in conjunction with mainstream pharmaceuticals, with encouraging outcomes. In this article, we look at the latest research on the usage of natural products to alleviate the severity of COVID-19. To determine the activity of the natural products, act against SARS-CoV-2 to various targets like Mpro, ACE-II, papain-like, chymotrypsin-like proteases, and some antiviral targets. The processes underlying this preventative or therapeutic action are also examined. We used PubMed, Scopus, Google Scholar, and the WHO site to perform our review. The anti-SARS-CoV-2 impacts of various herbal extracts and purified compounds may be mediated via direct prevention of viral replication or entrance. Interestingly, certain items might avert SARS-CoV-2 from infecting human cells by blocking the ACE-2 protein or the serine protease TMPRRS2. Natural products have also been stated to suppress proteins intricate in the virus life cycle, like papain-like and chymotrypsin-like proteases. To conclude, natural products can be used alone or in combination as remedies or treatments for COVID-19. In addition, their compositions may provide insight into the development of effective and reliable antiviral drugs.

Identification of Papain-Like Protease inhibitors of SARS CoV-2 through HTVS, Molecular docking, MMGBSA and Molecular dynamics approach.

Coronaviruses (CoVs) are a large group of enveloped positive sense single-stranded RNA viruses that can cause disease to humans. These are zoonotic having potential to cause large-scale outbreaks of infections widely causing morbidity and mortality. Papain-Like Proteases (PLpro) is a cysteine protease, essential for viral replication and proliferation, as a highly conserved enzyme it cleaves peptide linkage between Nsp1, Nsp2, Nsp3, and Nsp4. As a valid therapeutic targets it stops viral reproduction and boosts host immune response thereby halting further spread of infection. In the purpose of identifying inhibitors targeting Papain-Like Proteases (PLpro) we initiated a high throughput virtual screening (HTVS) protocol using a SuperNatural Database. The XP docking results revealed that two compounds SN00334175 and SN00162745 exhibited docking score of -10.58 kcal/mol and -9.93 kcal/mol respectively. The Further PRIME MMGB-SA studies revealed Van der Waal energy and hydrophobic energy terms as major contributors for total binding free energy. The 100 ns molecular dynamics simulation of SN00334175/7JN2 and SN00162745/7JN2 revealed that these complexes were stabilized with ligand binding forming interactions with Gly266, Asn267, Tyr268, Tyr273, Thr301 and Asp302, Lys157, Leu162, Asp164, Arg166, Glu167, Pro248, Tyr264.

Identification of some novel oxazine substituted 9-anilinoacridines as SARS-CoV-2 inhibitors for COVID-19 by molecular docking, free energy calculation and molecular dynamics studies.

Coronavirus disease (COVID-19), a life-threatening disease, is caused by SARS-CoV-2. The targeted therapeutics of small molecules helps the scientific community to fight against SARS-CoV-2. In this article, some oxazine substituted 9-anilinoacridines (A1-A48) was designed by docking, MM-GBSA and molecular dynamics (MD) simulation studies for their COVID-19 inhibitory activity. The docking of ligands A1-A48 against SARS-CoV-2 (PDB ID: 5R82) are performed by using Glide module, in silico ADMET screening by QikProp module, binding energy using Prime MM-GB/SA module, MD simulation by Desmond module and atomic charges were derived by Jaguar module of Schrodinger suit 2019-4. Compound A38 has the highest G-score (-7.83) when compared to all the standard compounds which are proposed for COVID-19 treatment such as ritonavir (-7.48), lopinavir (-6.94), nelfinavir (-5.93), hydroxychloroquine (-5.47) and mataquine (-5.37). Compounds A13, A23, A18, A7, A48, A46, A32, A20, A1 and A47 are significantly active against SARS-CoV-2 main protease when compared with hydroxychloroquine and mataquine. The residues GLN19, THR24, THR25, THR26, LEU27, HIE41, SER46, MET49, ASN119, ASN142, HIE164, MET165, ASP187, ARG188 and GLN189 of SARS-CoV-2 main protease play a crucial role in binding with ligands. The in silico ADMET properties of the molecules are within the recommended values. The binding free energy was calculated using PRIME MM-GB/SA studies. From the ligands A38, A13, A23, A18, A7, A48 and A46 with significant Glide scores may produce significant COVID-19 activity for further development. Compound A38 was subjected to MD simulation at 100 ns to study the dynamic behaviour of protein-ligand complex.Communicated by Ramaswamy H. Sarma.