In-silico drug repurposing for targeting SARS-CoV-2 main protease (Mpro).
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ABSTRACT:
SUBMITTER: Sharma S
PROVIDER: S-EPMC7678360 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and aimsSevere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) induced Novel Coronavirus Disease (COVID-19) has currently become pandemic worldwide. Though drugs like remdesivir, favipiravir, and dexamethasone found beneficial for COVID-19 management, they have limitations clinically, and vaccine development takes a long time. The researchers have reported key proteins which could act as druggable targets. Among them, the major protease Mpro is first published, plays a prominent role in viral replication and an attractive drug-target for drug discovery. Hence, to target Mpro and inhibit it, we accomplished the virtual screening of US-FDA approved drugs using well-known drug repurposing approach by computer-aided tools.MethodsThe protein Mpro, PDB-ID 6LU7 was imported to Maestro graphical user interphase of Schrödinger software. The US-FDA approved drug structures are imported from DrugBank and docked after preliminary protein and ligand preparation. The drugs are shortlisted based on the docking scores in the Standard Precision method (SP-docking) and then based on the type of molecular interactions they are studied for molecular dynamics simulations.ResultsThe docking and molecular interactions studies, five drugs emerged as potential hits by forming hydrophilic, hydrophobic, electrostatic interactions. The drugs such as arbutin, terbutaline, barnidipine, tipiracil and aprepitant identified as potential hits. Among the drugs, tipiracil and aprepitant interacted with the Mpro consistently, and they turned out to be most promising.ConclusionsThis study shows the possible exploration for drug repurposing using computer-aided docking tools and the potential roles of tipiracil and aprepitant, which can be explored further in the treatment of COVID-19.
| S-EPMC7498210 | biostudies-literature
Project description:The main protease (Mpro or 3CLpro) is a conserved cysteine protease from the coronaviruses and started to be considered an important drug target for developing antivirals, as it produced a deadly outbreak of COVID-19. Herein, we used a combination of drug reposition and computational modeling approaches including molecular docking, molecular dynamics (MD) simulations, and the calculated binding free energy to evaluate a set of drugs in complex with the Mpro enzyme. Particularly, our results show that darunavir and triptorelin drugs have favorable binding free energy (-63.70 and -77.28 kcal mol-1, respectively) in complex with the Mpro enzyme. Based on the results, the structural and energetic features that explain why some drugs can be repositioned to inhibit Mpro from SARS-CoV-2 were exposed. These features should be considered for the design of novel Mpro inhibitors.
| S-EPMC9036595 | biostudies-literature
Project description:The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome - novel Coronavirus 2 (SARS-CoV-2). SARS-CoV-2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-CoV, which caused SARS in the year 2002-2003. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-CoV-2. The high-resolution crystal structure of the main protease of SARS-CoV-2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 μs open-source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for the main protease helped in exploring the conformational variation in the drug-binding site of the main protease leading to the efficient binding of more relevant drug molecules. The drugs obtained as top hits from the ensemble docking possessed anti-bacterial and anti-viral properties. This in silico ensemble docking approach would support the identification of potential candidates for repurposing against COVID-19.Communicated by Ramaswamy H. Sarma.
| S-EPMC7441806 | biostudies-literature
Project description:This article highlights recent pioneering work by Günther et al. towards the discovery of potential repurposed antiviral compounds (peptidomimetic and non-peptidic) against the SARS-CoV-2 main protease (Mpro ). The antiviral activity of the most potent drugs is discussed along with their binding mode to Mpro as observed through X-ray crystallographic screening.
| S-EPMC8652770 | biostudies-literature
Project description:The recent emergence of the severe acute respiratory disease caused by a novel coronavirus remains a concern posing many challenges to public health and the global economy. The resolved crystal structure of the main protease of SARS-CoV-2 or SCV2 (Mpro) has led to its identification as an attractive target for designing potent antiviral drugs. Herein, we provide a comparative molecular impact of hydroxychloroquine (HCQ), remdesivir, and β-D-N4-Hydroxycytidine (NHC) binding on SCV2 Mpro using various computational approaches like molecular docking and molecular dynamics (MD) simulation. Data analyses showed that HCQ, remdesivir, and NHC binding to SARS-CoV-2 Mpro decrease the protease loop capacity to fluctuate. These binding influences the drugs’ optimum orientation in the conformational space of SCV2 Mpro and produce noticeable steric effects on the interactive residues. An increased hydrogen bond formation was observed in SCV2 Mpro–NHC complex with a decreased receptor residence time during NHC binding. The binding mode of remdesivir to SCV2 Mpro differs from other drugs having van der Waals interaction as the force stabilizing protein–remdesivir complex. Electrostatic interaction dominates in the SCV2 Mpro−HCQ and SCV2 Mpro–NHC. Residue Glu166 was highly involved in the stability of remdesivir and NHC binding at the SCV2 Mpro active site, while Asp187 provides stability for HCQ binding.
| S-EPMC10036164 | biostudies-literature
Project description:In the present situation, COVID-19 has become the global health concern due to its high contagious nature. It initially appeared in December 2019 in Wuhan, China and now affected more than 190 countries. As of now preventive measures are the sole solution to stop this disease for further transmission from person to person transmissions as there is no effective treatment or vaccine available to date. Research and development of new molecule is a laborious process; therefore, drug repurposing can be an alternative solution that involves the identification of potential compounds from the already available data. Alkaloids are potential source of therapeutic agents which might be able to treat novel COVID-19. Therefore, in the present study, twenty potential alkaloid molecules that possess antiviral activity against different viral diseases have taken into consideration and scrutinized using Lipinski's rule. Then out of twenty compounds seventeen were further selected for docking study. Docking study was performed using Autodock software and the best four molecule which provides maximum negative binding energy was selected for further analysis. Two alkaloids namely thalimonine and sophaline D showed potential activity to inhibit the Mpro but to confirm the claim further in-vitro studies are required.
| S-EPMC7649659 | biostudies-literature
Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants are responsible for the devastating coronavirus disease 2019 (COVID-19) pandemic with more than 6.5 million deaths since 2019. Although a number of vaccines significantly reduced the mortality rate, a large number of the world population is yet being infected with highly contagious omicron variants/subvarints. Additional therapeutic interventions are needed to reduce hospitalization and curb the ongoing pandemic. The activity of the SARS-CoV-2 enzyme; chymotrypsin-like main protease (Mpro) is essential for the cleavage of viral nonstructural polypeptides into individual functional proteins and therefore Mpro is an attractive drug target. The aim of this review is to summarize recent progress toward the development of therapeutic drugs against Mpro protease.
| S-EPMC9773221 | biostudies-literature
Project description:The coronavirus disease, COVID-19, is the major focus of the whole world due to insufficient treatment options. It has spread all around the world and is responsible for the death of numerous human beings. The future consequences for the disease survivors are still unknown. Hence, all contributions to understand the disease and effectively inhibit the effects of the disease have great importance. In this study, different thioxanthone based molecules, which are known to be fluorescent compounds, were selectively chosen to study if they can inhibit the main protease of SARS-CoV-2 using various computational tools. All candidate ligands were optimized, molecular docking and adsorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were conducted and subsequently, some were subjected to 100 ns molecular dynamics simulations in conjunction with the known antiviral drugs, favipiravir, and hydroxychloroquine. It was found that different functional groups containing thioxanthone based molecules are capable of different intermolecular interactions. Even though most of the studied ligands showed stable interactions with the main protease, para-oxygen-di-acetic acid functional group containing thioxanthone was found to be a more effective inhibitor due to the higher number of intermolecular interactions and higher stability during the simulations.
| S-EPMC10388053 | biostudies-literature
Project description:SARS-CoV-2 Main protease (Mpro) is a well-known drug target against SARS-CoV-2 infection. Identification of Mpro inhibitors is vigorously pursued due to its crucial role in viral replication. The present study was aimed to identify Mpro inhibitors via repurposing of US-FDA approved drugs by STD-NMR spectroscopy. In this study, 156 drugs and natural compounds were evaluated against Mpro. Among them, 10 drugs were found to be interacting with Mpro, including diltiazem HCl (1), mefenamic acid (2), losartan potassium (3), mexiletine HCl (4), glaucine HBr (5), trimebutine maleate (6), flurbiprofen (7), amantadine HCl (8), dextromethorphan (9), and lobeline HCl (10) in STD-NMR spectroscopy. Their interactions were compared with three standards (Repurposed anti-viral drugs), dexamethasone, chloroquine phosphate, and remdesivir. Thermal stability of Mpro and dissociation constant (Kd) of six interacting drugs were also determined using DSF. RMSD plots in MD simulation studies showed the formation of stable protein-ligand complexes. They were further examined for their antiviral activity by plaque reduction assay against SARS-CoV-2, which showed 55-100% reduction in viral plaques. This study demonstrates the importance of drug repurposing against emerging and neglected diseases. This study also exhibits successful application of STD-NMR spectroscopy combined with plaque reduction assay in rapid identification of potential anti-viral agents.
| S-EPMC9896891 | biostudies-literature
Project description:Herein, the DrugBank database which contains 10,036 approved and investigational drugs was explored deeply for potential drugs that target SARS-CoV-2 main protease (Mpro). Filtration process of the database was conducted using three levels of accuracy for molecular docking calculations. The top 35 drugs with docking scores > -11.0 kcal/mol were then subjected to 10 ns molecular dynamics (MD) simulations followed by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. The results showed that DB02388 and Cobicistat (DB09065) exhibited potential binding affinities towards Mpro over 100 ns MD simulations, with binding energy values of -49.67 and -46.60 kcal/mol, respectively. Binding energy and structural analyses demonstrated the higher stability of DB02388 over Cobicistat. The potency of DB02388 and Cobicistat is attributed to their abilities to form several hydrogen bonds with the essential amino acids inside the active site of Mpro. Compared to DB02388 and Cobicistat, Darunavir showed a much lower binding affinity of -34.83 kcal/mol. The present study highlights the potentiality of DB02388 and Cobicistat as anti-COVID-19 drugs for clinical trials. Communicated by Ramaswamy H. Sarma.
| S-EPMC7441803 | biostudies-literature