Traditional medicinal plants against replication, maturation and transmission targets of SARS-CoV-2: computational investigation.
ABSTRACT: COVID-19 is an infectious pandemic caused by the SARS-CoV-2 virus. The critical components of SARS-CoV-2 are the spike protein (S-protein) and the main protease (Mpro). Mpro is required for the maturation of the various polyproteins involved in replication and transcription. S-protein helps the SARS-CoV-2 to enter the host cells through the angiotensin-converting enzyme 2 (ACE2). Since ACE2 is required for the binding of SARS-CoV-2 on the host cells, ACE2 inhibitors and blockers have got wider attention, in addition to S-protein and Mpro modulators as potential therapeutics for COVID-19. So far, no specific drugs have shown promising therapeutic potential against COVID-19. The current study was undertaken to evaluate the therapeutic potential of traditional medicinal plants against COVID-19. The bioactives from the medicinal plants, along with standard drugs, were screened for their binding against S-protein, Mpro and ACE2 targets using molecular docking followed by molecular dynamics. Based on the higher binding affinity compared with standard drugs, bioactives were selected and further analyzed for their pharmacological properties such as drug-likeness, ADME/T-test, biological activities using in silico tools. The binding energies of several bioactives analyzed with target proteins were relatively comparable and even better than the standard drugs. Based on Lipinski factors and lower binding energies, seven bioactives were further analyzed for their pharmacological and biological characteristics. The selected bioactives were found to have lower toxicity with a higher GI absorption rate and potent anti-inflammatory and anti-viral activities against targets of COVID-19. Therefore, the bioactives from these medicinal plants can be further developed as phytopharmaceuticals for the effective treatment of COVID-19.
Project description:The current COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its variants, remains a serious health hazard globally. The SARS-CoV-2 Mpro and spike proteins, as well as the human ACE2 receptor, have previously been reported as good targets for the development of new drug leads to combat COVID-19. Various ligands, including synthetic and plant-derived small molecules, can interact with the aforementioned proteins. In this study, we investigated the interaction of eight phytochemicals, from selected medicinal plants (Aegle marmelos, Azadirachta indica, and Ocimum sanctum) commonly used in Indian traditional medicine, with SARS-CoV-2 Mpro (PDBID: 6LU7), SARS-CoV-2S spike protein (PDB ID: 6M0J) and the human ACE2 receptor (PDB ID: 6M18). All compounds were subjected to density functional theory (DFT) and frontier molecular orbitals (FMO) analysis to determine their geometry, and key electronic and energetic properties. Upon examining the interactions of the phytochemicals with the human ACE2 receptor and the SARS-CoV-2 Mpro, spike protein targets, two compounds (C-5 and C-8) were identified as the best binding ligands. These were further examined in MD simulation studies to determine the stability of the ligand–protein interactions. QSAR, pharmacokinetic and drug-likeness properties studies revealed that C-5 may be the best candidate to serve as a template for the design and development of new drugs to combat COVID-19.
Project description:<h4>Background</h4>Coronavirus disease-2019 (COVID-19) is an infectious pandemic caused by SARS-CoV-2. SARS-CoV-2 main protease (M<sup>pro</sup>) and spike protein are crucial for viral replication and transmission. Spike protein recognizes the human ACE2 receptor and transmits SARS-CoV-2 into the human body. Thus, M<sup>pro</sup>, spike protein, and ACE2 receptor act as appropriate targets for the development of therapeutics against SARS-CoV-2. Spices are traditionally known to have anti-viral and immune-boosting activities. Therefore, we investigated the possible use of selected spice bioactives against the potential targets of SARS-CoV-2 using computational analysis.<h4>Methods</h4>Molecular docking analysis was performed to analyze the binding efficiency of spice bioactives against SARS-CoV-2 target proteins along with the standard drugs. Drug-likeness properties of selected spice bioactives were investigated using Lipinski's rule of five and the SWISSADME database. Pharmacological properties such as ADME/T, biological functions, and toxicity were analyzed using ADMETlab, PASS-prediction, and ProTox-II servers, respectively.<h4>Results</h4>Out of forty-six spice bioactives screened, six bioactives have shown relatively better binding energies than the standard drugs and have a higher binding affinity with at least more than two targets of SARS-CoV-2. The selected bioactives were analyzed for their binding similarities with the standard drug, remdesivir, towards the targets of SARS-CoV-2. Selected spice bioactives have shown potential drug-likeness properties, with higher GI absorption rate, lower toxicity with pleiotropic biological roles.<h4>Conclusions</h4>Spice bioactives have the potential to bind with the specific targets involved in SARS-CoV-2 infection and transmission. Therefore, spice-based nutraceuticals can be developed for the prevention and treatment of COVID-19.
Project description:<h4>Background</h4>Identification and repurposing of therapeutic and preventive strategies against COVID-19 are rapidly undergoing. Several medicinal plants from the Himalayan region have been traditionally used to treat various human disorders. Thus, in our current study, we intended to explore the potential ability of Himalayan medicinal plant (HMP) bioactives against COVID-19 using computational investigations.<h4>Methods</h4>Molecular docking was performed against six crucial targets involved in the replication and transmission of SARS-CoV-2. About forty-two HMP bioactives were analyzed against these targets for their binding energy, molecular interactions, inhibition constant, and biological pathway enrichment analysis. Pharmacological properties and potential biological functions of HMP bioactives were predicted using the ADMETlab and PASS webserver respectively.<h4>Results</h4>Our current investigation has demonstrated that the bioactives of HMPs potentially act against COVID-19. Docking results showed that several HMP bioactives had a superior binding affinity with SARS-CoV-2 essential targets like 3CL<sup>pro</sup>, PLpro, RdRp, helicase, spike protein, and human ACE2. Based on the binding energies, several bioactives were selected and analyzed for pathway enrichment studies. We have found that selected HMP bioactives may have a role in regulating immune and apoptotic pathways. Furthermore, these selected HMP bioactives have shown lower toxicity with pleiotropic biological activities, including anti-viral activities in predicting activity spectra for substances.<h4>Conclusions</h4>Current study results can explore the possibility of HMPs as therapeutic agents against COVID-19.
Project description:Coronavirus disease 2019 (COVID-19) is a highly transmissible viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical trials have reported improved outcomes resulting from an effective reduction or absence of viral load when patients were treated with chloroquine (CQ) or hydroxychloroquine (HCQ). In addition, the effects of these drugs were improved by simultaneous administration of azithromycin (AZM). The receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein binds to the cell surface angiotensin-converting enzyme 2 (ACE2) receptor, allowing virus entry and replication in host cells. The viral main protease (Mpro) and host cathepsin L (CTSL) are among the proteolytic systems involved in SARS-CoV-2 S protein activation. Hence, molecular docking studies were performed to test the binding performance of these three drugs against four targets. The findings showed AZM affinity scores (?G) with strong interactions with ACE2, CTSL, Mpro and RBD. CQ affinity scores showed three low-energy results (less negative) with ACE2, CTSL and RBD, and a firm bond score with Mpro. For HCQ, two results (ACE2 and Mpro) were firmly bound to the receptors, however CTSL and RBD showed low interaction energies. The differences in better interactions and affinity between HCQ and CQ with ACE2 and Mpro were probably due to structural differences between the drugs. On other hand, AZM not only showed more negative (better) values in affinity, but also in the number of interactions in all targets. Nevertheless, further studies are needed to investigate the antiviral properties of these drugs against SARS-CoV-2.
Project description:In the present study, we have explored the interaction of the active components from 10 different medicinal plants of Indian origin that are commonly used for treating cold and respiratory-related disorders, through molecular docking analysis. In the current scenario, COVID-19 patients experience severe respiratory syndromes, hence it is envisaged from our study that these traditional medicines are very likely to provide a favourable effect on COVID-19 infections. The active ingredients identified from these natural products are previously reported for antiviral activities against large group of viruses. Totally 47 bioactives identified from the medicinal plants were investigated against the structural targets of SARS-CoV-2 (Mpro and spike protein) and human ACE2 receptor. The top leads were identified based on interaction energies, number of hydrogen bond and other parameters that explain their potency to inhibit SARS-CoV-2. The bioactive ligands such as Cucurbitacin E, Orientin, Bis-andrographolide, Cucurbitacin B, Isocucurbitacin B, Vitexin, Berberine, Bryonolic acid, Piperine and Magnoflorine targeted the hotspot residues of SARS-CoV-2 main protease. In fact, this protease enzyme has an essential role in mediating the viral replication and therefore compounds targeting this key enzyme are expected to block the viral replication and transcription. The top scoring conformations identified through docking analysis were further demonstrated with molecular dynamics simulation. Besides, the stability of the conformation was studied in detail by investigating the binding free energy using MM-PBSA method. Overall, the study emphasized that the proposed hit Cucurbitacin E and orientin could serve as a promising scaffold for developing anti-COVID-19 drug.Communicated by Ramaswamy H. Sarma.
Project description:Due to the lack of efficient therapeutic options and clinical trial limitations, the FDA-approved drugs can be a good choice to handle Coronavirus disease (COVID-19). Many reports have enough evidence for the use of FDA-approved drugs which have inhibitory potential against target proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we utilized a structure-based drug design approach to find possible drug candidates from the existing pool of FDA-approved drugs and checked their effectiveness against the SARS-CoV-2. We performed virtual screening of the FDA-approved drugs against the main protease (Mpro) of SARS-CoV-2, an essential enzyme, and a potential drug target. Using well-defined computational methods, we identified Glecaprevir and Maraviroc (MVC) as the best inhibitors of SARS-CoV-2 Mpro. Both drugs bind to the substrate-binding pocket of SARS-CoV-2 Mpro and form a significant number of non-covalent interactions. Glecaprevir and MVC bind to the conserved residues of substrate-binding pocket of SARS-CoV-2 Mpro. This work provides sufficient evidence for the use of Glecaprevir and MVC for the therapeutic management of COVID-19 after experimental validation and clinical manifestations.
Project description:Coronavirus Disease-2019 (COVID-19), a viral disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was declared a global pandemic by WHO in 2020. In this scenario, SARS-CoV-2 main protease (COVID-19 M<sup>pro</sup>), an enzyme mainly involved in viral replication and transcription is identified as a crucial target for drug discovery. Traditionally used medicinal plants contain a large amount of bioactives and pave a new path to develop drugs and medications for COVID-19. The present study was aimed to examine the potential of Emblica officinalis (amla), Phyllanthus niruri Linn. (bhumi amla) and Tinospora cordifolia (giloy) bioactive compounds to inhibit the enzymatic activity of COVID-19 M<sup>pro</sup>. In total, 96 bioactive compounds were selected and docked with COVID-19 M<sup>pro</sup> and further validated by molecular dynamics study. From the docking and molecular dynamics study, it was revealed that the bioactives namely amritoside, apigenin-6-C-glucosyl7-O-glucoside, pectolinarin and astragalin showed better binding affinities with COVID-19 M<sup>pro</sup>. Drug-likeness, ADEMT and bioactivity score prediction of best drug candidates were evaluated by DruLiTo, pkCSM and Molinspiration servers, respectively. Overall, the in silico results confirmed that the validated bioactives could be exploited as promising COVID-19 M<sup>pro</sup> inhibitors.
Project description:The current COVID-19 pandemic is caused by SARS CoV-2. To date, ∼463,000 people died worldwide due to this disease. Several attempts have been taken in search of effective drugs to control the spread of SARS CoV-2 infection. The main protease (Mpro) from SARS CoV-2 plays a vital role in viral replication and thus serves as an important drug target. This Mpro shares a high degree of sequence similarity (>96%) with the same protease from SARS CoV-1 and MERS. It was already reported that <i>Broussonetia papyrifera</i> polyphenols efficiently inhibit the catalytic activity of SARS CoV-1 and MERS Mpro. But whether these polyphenols exhibit any inhibitory effect on SARS CoV-2 Mpro is far from clear. To understand this fact, here we have adopted computational approaches. Polyphenols having proper drug-likeness properties and two repurposed drugs (lopinavir and darunavir; having binding affinity -7.3 to -7.4 kcal/mol) were docked against SARS CoV-2 Mpro to study their binding properties. Only six polyphenols (broussochalcone A, papyriflavonol A, 3'-(3-methylbut-2-enyl)-3',4',7-trihydroxyflavane, broussoflavan A, kazinol F and kazinol J<b>)</b> had interaction with both the catalytic residues (His41 and Cys145) of Mpro and exhibited good binding affinity (-7.6 to -8.2 kcal/mol). Molecular dynamic simulations (100 ns) revealed that all Mpro-polyphenol complexes are more stable, conformationally less fluctuated; slightly less compact and marginally expanded than Mpro-darunavir/lopinavir complex. Even the number of intermolecular H-bond and MM-GBSA analysis suggested that these six polyphenols are more potent Mpro inhibitors than the two repurposed drugs (lopinavir and darunavir) and may serve as promising anti-COVID-19 drugs. Communicated by Ramaswamy H. Sarma.
Project description:As per the World Health Organization report, around 226 844 344 confirmed positive cases and 4 666 334 deaths are reported till September 17, 2021 due to the recent viral outbreak. A novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) is responsible for the associated coronavirus disease (COVID-19), which causes serious or even fatal respiratory tract infection and yet no approved therapeutics or effective treatment is currently available to combat the outbreak. Due to the emergency, the drug repurposing approach is being explored for COVID-19. In this study, we attempt to understand the potential mechanism and also the effect of the approved antiviral drugs against the SARS-CoV-2 main protease (Mpro). To understand the mechanism of inhibition of the malaria drug hydroxychloroquine (HCQ) against SARS-CoV-2, we performed molecular interaction studies. The studies revealed that HCQ docked at the active site of the Human ACE2 receptor as a possible way of inhibition. Our in silico analysis revealed that the three drugs Lopinavir, Ritonavir, and Remdesivir showed interaction with the active site residues of Mpro. During molecular dynamics simulation, based on the binding free energy contributions, Lopinavir showed better results than Ritonavir and Remdesivir.
Project description:No commercially available drug candidate has yet been devised which is unique to and not repurposed against SARS-CoV-2 and has high efficacy or safe toxicity profile or both. Taking curcumin as a reference compound, we identified a new commercially available cyclohexanone compound, ZINC07333416 with binding energy (-8.72 kcal/mol) better than that of popularly devised anti-Covid-19 drugs like viral protease inhibitor Lopinavir, nucleoside analogue Remdesivir and the repurposed drug hydroxychloroquine when targeted to the active-site of SARS-CoV-2 Main protease (Mpro) through docking studies. The ligand ZINC07333416 exhibits crucial interactions with major active site residues of SARS-CoV-2 Mpro viz. Cys145 and His41 involving in the protease activity; as well as GLU-166 and ASN-142 which plays the pivotal role in the protein-dimerization. The protein-ligand stable interaction was further confirmed with molecular dynamics simulation (MDS) studies. Based on virtual assessment, ZINC07333416 also have significant values in terms of medicinal chemistry, pharmacokinetics, synthetic accessibility and anti-viral activity that encourage its experimental applications against COVID-19.