In silico modeling for quick prediction of inhibitory activity against 3CLpro enzyme in SARS CoV diseases.
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SUBMITTER: De P
PROVIDER: S-EPMC7544940 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundSevere acute respiratory syndrome (SARS) has been initiating pandemics since the beginning of the century. In December 2019, the world was hit again by a devastating SARS episode that has so far infected almost four million individuals worldwide, with over 200,000 fatalities having already occurred by mid-April 2020, and the infection rate continues to grow exponentially. SARS coronavirus 2 (SARS-CoV-2) is a single stranded RNA pathogen which is characterised by a high mutation rate. It is vital to explore the mutagenic capability of the viral genome that enables SARS-CoV-2 to rapidly jump from one host immunity to another and adapt to the genetic pool of local populations.MethodsFor this study, we analysed 2301 complete viral sequences reported from SARS-CoV-2 infected patients. SARS-CoV-2 host genomes were collected from The Global Initiative on Sharing All Influenza Data (GISAID) database containing 9 genomes from pangolin-CoV origin and 3 genomes from bat-CoV origin, Wuhan SARS-CoV2 reference genome was collected from GeneBank database. The Multiple sequence alignment tool, Clustal Omega was used for genomic sequence alignment. The viral replicating enzyme, 3-chymotrypsin-like cysteine protease (3CLpro) that plays a key role in its pathogenicity was used to assess its affinity with pharmacological inhibitors and repurposed drugs such as anti-viral flavones, biflavanoids, anti-malarial drugs and vitamin supplements.ResultsOur results demonstrate that bat-CoV shares > 96% similar identity, while pangolin-CoV shares 85.98% identity with Wuhan SARS-CoV-2 genome. This in-depth analysis has identified 12 novel recurrent mutations in South American and African viral genomes out of which 3 were unique in South America, 4 unique in Africa and 5 were present in-patient isolates from both populations. Using state of the art in silico approaches, this study further investigates the interaction of repurposed drugs with the SARS-CoV-2 3CLpro enzyme, which regulates viral replication machinery.ConclusionsOverall, this study provides insights into the evolving mutations, with implications to understand viral pathogenicity and possible new strategies for repurposing compounds to combat the nCovid-19 pandemic.
| S-EPMC7344048 | biostudies-literature
Project description:Molecular docking results of two training sets containing 866 and 8,696 compounds were used to train three different machine learning (ML) approaches. Neural network approaches according to Keras and TensorFlow libraries and the gradient boosted decision trees approach of XGBoost were used with DScribe's Smooth Overlap of Atomic Positions molecular descriptors. In addition, neural networks using the SchNetPack library and descriptors were used. The ML performance was tested on three different sets, including compounds for future organic synthesis. The final evaluation of the ML predicted docking scores was based on the ZINC in vivo set, from which 1,200 compounds were randomly selected with respect to their size. The results obtained showed a consistent ML prediction capability of docking scores, and even though compounds with more than 60 atoms were found slightly overestimated they remain valid for a subsequent evaluation of their drug repurposing suitability.
| S-EPMC8881816 | biostudies-literature
Project description:The emergence of the Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to over 6 million deaths. The 3C-like protease (3CLpro) enzyme of the SARS-CoV-2 virus is an attractive druggable target for exploring therapeutic drug candidates to combat COVID-19 due to its key function in viral replication. Marine natural products (MNPs) have attracted considerable attention as alternative sources of antiviral drug candidates. In looking for potential 3CLpro inhibitors, the MNP database (>14,000 molecules) was virtually screened against 3CLpro with the assistance of molecular docking computations. The performance of AutoDock and OEDocking software in anticipating the ligand-3CLpro binding mode was first validated according to the available experimental data. Based on the docking scores, the most potent MNPs were further subjected to molecular dynamics (MD) simulations, and the binding affinities of those molecules were computed using the MM-GBSA approach. According to MM-GBSA//200 ns MD simulations, chetomin (UMHMNP1403367) exhibited a higher binding affinity against 3CLpro than XF7, with ΔGbinding values of −55.5 and −43.7 kcal/mol, respectively. The steadiness and tightness of chetomin with 3CLpro were evaluated, revealing the high stabilization of chetomin (UMHMNP1403367) inside the binding pocket of 3CLpro throughout 200 ns MD simulations. The physicochemical and pharmacokinetic features of chetomin were also predicted, and the oral bioavailability of chetomin was demonstrated. Furthermore, the potentiality of chetomin analogues −namely, chetomin A-D− as 3CLpro inhibitors was investigated. These results warrant further in vivo and in vitro assays of chetomin (UMHMNP1403367) as a promising anti-COVID-19 drug candidate.
| S-EPMC9866112 | biostudies-literature
Project description:The porcine epidemic diarrhea virus (PEDV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are two highly pathogenic viruses causing tremendous damages to the swine and human populations, respectively. Vaccines are available to prevent contamination and to limit dissemination of these two coronaviruses, but efficient and widely affordable treatments are needed. Recently, four natural products targeting the 3C-like protease (3CLpro) of PEDV and inhibiting replication of the virus in vitro have been identified: tomatidine, epigallocatechin-3-gallate, buddlejasaponin IVb and pneumocandin B0. We have evaluated the interaction of these compounds with 3CLpro of PEDV and with the structurally similar main protease (Mpro) of SARS-CoV-2. The molecular docking analysis indicated that the echinocandin-type lipopeptide pneumocandin B0 can generate much more stable complexes with both proteases compared to tomatidine. The empirical energy of interaction (ΔE) calculated with pneumocandin B0 bound to Mpro is extremely high, comparable to that measured with known antiviral drugs. Pneumocandin B0 and its analogue capsofungin appeared a little less adapted to interact with 3CLpro compared to Mpro. In contrast, the antifungal drug micafungin bearing an unfused tricyclic side chain, emerges as a better ligand of 3CLpro of PEDV compared to Mpro of SARS-CoV-2, based on our calculations. Collectively, the analysis underlines the benefit of echinocandin-type antifungal drugs as potential inhibitors of PEDV and SARS-CoV-2 main proteases. These clinically important antifungal natural products deserve further studies as antiviral agents.
| S-EPMC8248761 | biostudies-literature
Project description:COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus 2. Presently, there is no effective treatment for COVID-19. As part of the worldwide efforts to find efficient therapies and preventions, it has been reported the crystalline structure of the SARS-CoV-2 main protease Mpro (also called 3CLpro) bound to a synthetic inhibitor, which represents a major druggable target. The druggability of Mpro could be used for discovering drugs to treat COVID-19. A multilevel computational study was carried out to evaluate the potential antiviral properties of the components of the medicinal herb Uncaria tomentosa (Cat's claw), focusing on the inhibition of Mpro. The in silico approach starts with protein-ligand docking of 26 Cat's claw key components, followed by ligand pathway calculations, molecular dynamics simulations, and MM-GBSA calculation of the free energy of binding for the best docked candidates. The structural bioinformatics approaches led to identification of three bioactive compounds of Uncaria tomentosa (speciophylline, cadambine, and proanthocyanidin B2) with potential therapeutic effects by strong interaction with 3CLpro. Additionally, in silico drug-likeness indices for these components were calculated and showed good predicted therapeutic profiles of these phytochemicals. Our findings suggest the potential effectiveness of Cat's claw as complementary and/or alternative medicine for COVID-19 treatment.
| S-EPMC7532411 | biostudies-literature
Project description:3CLpro is the main protease of the novel coronavirus (SARS-CoV-2) responsible for their intracellular duplication. Based on virtual screening technology and molecular dynamics simulation, we found 23 approved clinical drugs such as Viomycin, Capastat, Carfilzomib and Saquinavir, which showed high affinity with the 3CLpro active sites. These findings showed that there were potential drugs that inhibit SARS-Cov-2's 3CLpro in the current clinical drug library, and these drugs can be further tested or chemically modified for the treatment of COVID-19.Communicated by Ramaswamy H. Sarma.
| S-EPMC7544985 | biostudies-literature
Project description:The pandemic, COVID-19, has spread worldwide and affected millions of people. There is an urgent need, therefore, to find a proper treatment for the novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the causative agent. This paper focuses on identifying inhibitors that target SARS-CoV-2 proteases, PLPRO and 3CLPRO, which control the duplication and manages the life cycle of SARS-CoV-2. We have carried out detailed in silico Virtual high-throughput screening using Food and Drug Administration (FDA) approved drugs from the Zinc database, COVID-19 clinical trial compounds from Pubchem database, Natural compounds from Natural Product Activity and Species Source (NPASS) database and Maybridge database against PLPRO and 3CLPRO proteases. After thoroughly analyzing the screening results, we found five compounds, Bemcentinib, Pacritinib, Ergotamine, MFCD00832476, and MFCD02180753 inhibit PLPRO and six compounds, Bemcentinib, Clofazimine, Abivertinib, Dasabuvir, MFCD00832476, Leuconicine F inhibit the 3CLPRO. These compounds are stable within the protease proteins' active sites at 20ns MD simulation. The stability is revealed by hydrogen bond formations, hydrophobic interactions, and salt bridge interactions. Our study results also reveal that the selected five compounds against PLPRO and the six compounds against 3CLPRO bind to their active sites with good binding free energy. These compounds that inhibit the activity of PLPRO and 3CLPRO may, therefore, be used for treating COVID-19 infection.
| S-EPMC8018918 | biostudies-literature
Project description:Coronavirus 3C-like protease (3CLpro) is a crucial target for treating coronavirus diseases including COVID-19. Our preliminary screening showed that Ampelopsis grossedentata extract (AGE) displayed potent SARS-CoV-2-3CLpro inhibitory activity, but the key constituents with SARS-CoV-2-3CLpro inhibitory effect and their mechanisms were unrevealed. Herein, a practical strategy via integrating bioactivity-guided fractionation and purification, mass spectrometry-based peptide profiling and time-dependent biochemical assay, was applied to identify the crucial constituents in AGE and to uncover their inhibitory mechanisms. The results demonstrated that the flavonoid-rich fractions (10-17.5 min) displayed strong SARS-CoV-2-3CLpro inhibitory activities, while the constituents in these fractions were isolated and their SARS-CoV-2-3CLpro inhibitory activities were investigated. Among all isolated flavonoids, dihydromyricetin, isodihydromyricetin and myricetin strongly inhibited SARS-CoV-2 3CLpro in a time-dependent manner. Further investigations demonstrated that myricetin could covalently bind on SARS-CoV-2 3CLpro at Cys300 and Cys44, while dihydromyricetin and isodihydromyricetin covalently bound at Cys300. Covalent docking coupling with molecular dynamics simulations showed the detailed interactions between the orthoquinone form of myricetin and two covalent binding sites (surrounding Cys300 and Cys44) of SARS-CoV-2 3CLpro. Collectively, the flavonoids in AGE strongly and time-dependently inhibit SARS-CoV-2 3CLpro, while the newly identified SARS-CoV-2 3CLpro inhibitors in AGE offer promising lead compounds for developing novel antiviral agents.
| S-EPMC8322037 | biostudies-literature
Project description:Recently, an international randomized controlled clinical trial showed that patients with SARS-CoV-2 infection treated orally with the 3-chymotrypsin-like protease (3CLpro) inhibitor PF-07321332 within three days of symptom onset showed an 89% lower risk of COVID-19-related hospital admission/ death from any cause as compared with the patients who received placebo. Lending support to this critically important result of the aforementioned trial, we demonstrated in our study that patients infected with a SARS-Cov-2 sub-lineage (B.1.1.284) carrying the Pro108Ser mutation in 3CLpro tended to have a comparatively milder clinical course (i.e., a smaller proportion of patients required oxygen supplementation during the clinical course) than patients infected with the same sub-lineage of virus not carrying the mutation. Characterization of the mutant 3CLpro revealed that the Kcat/Km of the 3CLpro enzyme containing Ser108 was 58% lower than that of Pro108 3CLpro. Hydrogen/deuterium-exchange mass spectrometry (HDX-MS) revealed that the reduced activity was associated with structural perturbation surrounding the substrate-binding region of the enzyme, which is positioned behind and distant from the 108th amino acid residue. Our findings of the attenuated clinical course of COVID-19 in patients infected with SARS-CoV-2 strains with reduced 3CLpro enzymatic activity greatly endorses the promising result of the aforementioned clinical trial of the 3CLpro inhibitor.
| S-EPMC8789791 | biostudies-literature
Project description:The sudden increase in the COVID-19 epidemic affected by novel coronavirus 2019 has jeopardized public health worldwide. Hence the necessities of a drug or therapeutic agent that heal SARS-CoV-2 infections are essential requirements. The viral genome encodes a large Polyprotein, further processed by the main protease/ 3C-like protease (3CLpro) and papain-like proteases (PLpro) into 16 nonstructural proteins to form a viral replication complex. These essential functions of 3CLpro and PLpro in virus duplication make these proteases a promising target for discovering potential therapeutic candidates and possible treatment for SARS-CoV-2 infection. This study aimed to screen a unique set of protease inhibitors library against 3CLpro and PLpro of the SARS-CoV-2. A molecular docking study was performed using PyRx to reveal the binding affinity of the selected ligands and molecular dynamic simulations were executed to assess the three-dimensional stability of protein-ligand complexes. The pharmacodynamics parameters of the inhibitors were predicted using admetSAR. The top two ligands (Nafamostat and VR23) based on docking scores were selected for further studies. Selected ligands showed excellent pharmacokinetic properties with proper absorption, bioavailability and minimal toxicity. Due to the emerging and efficiency of remdesivir and dexamethasone in healing COVID-19 patients, ADMET properties of the selected ligands were thus compared with it. MD Simulation studies up to 100 ns revealed the ligands' stability at the target proteins' binding site residues. Therefore, Nafamostat and VR23 may provide potential treatment options against SARS-CoV-2 infections by potentially inhibiting virus duplication though more research is warranted.
| S-EPMC7884051 | biostudies-literature