Exploration of In-silico screening of therapeutic agents against SARS-CoV-2.
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ABSTRACT:
SUBMITTER: Thakur Y
PROVIDER: S-EPMC8416701 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Coronavirus disease 2019 (COVID-19) is a rapidly growing pandemic that requires urgent therapeutic intervention. Finding potential anti COVID-19 drugs aside from approved vaccines is progressively going on. The chemically diverse natural products represent valuable sources for drug leads. In this study, we aimed to find out safe and effective COVID-19 protease inhibitors from a library of natural products which share the main nucleus/skeleton of FDA-approved drugs that were employed in COVID-19 treatment guidelines or repurposed by previous studies. Our library was subjected to virtual screening against SARS-CoV Main protease (Mpro) using Molecular Operating Environment (MOE) software. Twenty-two out of those natural candidates showed higher binding scores compared to their analogues. We repurpose these natural products including alkaloids, glucosinolates, and phenolics as potential platforms for the development of anti-SARS-CoV-2 therapeutics. This study paves the way towards discovering a lead used in the treatment of COVID-19 from natural sources and introduces phytomedicines with dual therapeutic effects against COVID-19 besides their original pharmacological effects. We recommend further in vitro evaluation of their anti-COVID-19 activity and future clinical studies.
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Project description:SARS-CoV-2 represents the causative agent of the current pandemic (COVID-19). The drug repurposing technique is used to search for possible drugs that can bind to SARS-CoV-2 proteins and inhibit viral replication. In this study, the FDA-approved antiplatelets are tested against the main protease and spike proteins of SARS-CoV-2 using in silico methods. Molecular docking and molecular dynamics simulation are used in the current study. The results suggest the effectiveness of vorapaxar, ticagrelor, cilostazol, cangrelor, and prasugrel in binding the main protease (Mpro) of SARS-CoV-2. At the same time, vorapaxar, ticagrelor, and cilostazol are the best binders of the spike protein. Therefore, these compounds could be successful candidates against COVID-19 that need to be tested experimentally.
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Project description:COVID-19 has emerged as a rapidly escalating serious global health issue, affecting every section of population in a detrimental way. Present situation invigorated researchers to look for potent targets, development as well as repurposing of conventional therapeutic drugs. NSP12, a RNA polymerase, is key player in viral RNA replication and, hence, viral multiplication. In our study, we have screened a battery of FDA-approved drugs against SARS-CoV-2 RNA polymerase using in silico molecular docking approach. Identification of potent inhibitors against SARS-CoV-2 NSP12 (RNA polymerase) were screeened from FDA approved drugs by virtual screening for therapeutic applications in treatment of COVID-19. In this study, virtual screening of 1749 antiviral drugs was executed using AutoDock Vina in PyRx software. Binding affinities between NSP12 and drug molecules were determined using Ligplot+ and PyMOL was used for visualization of docking between interacting residues. Screening of 1749 compounds resulted in 14 compounds that rendered high binding affinity for NSP12 target molecule. Out of 14 compounds, 5 compounds which include 3a (Paritaprevir), 3d (Glecaprevir), 3h (Velpatasvir), 3j (Remdesivir) and 3l (Ribavirin) had a binding affinity of - 10.2 kcal/mol, -9.6 kcal/mol, - 8.5 kcal/mol, - 8.0 kcal/mol and - 6.8 kcal/mol, respectively. Moreover, a number of hydrophobic interactions and hydrogen bonding between these 5 compounds and NSP12 active site were observed. Further, 3l (Ribavirin) was docked with 6M71 and molecular dynamic simulation of the complex was also performed to check the stability of the conformation. In silico analysis postulated the potential of conventional antiviral drugs in treatment of COVID-19. However, these finding may be further supported by experimental data for its possible clinical application in present scenario.
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Project description:The epidemic of pneumonia (COVID-19) caused by novel coronavirus (SARS-CoV-2) infection has been listed as a public health emergency of international concern by the World Health Organization (WHO), and its harm degree is defined as a global "pandemic". At present, the efforts of various countries focus on the rapid diagnosis and isolation of patients, as well as to find a treatment that can combat the most serious impact of the disease. The number of reported COVID-19 virus infections is still increasing. Unfortunately, no drugs or vaccines have been approved for the treatment of human coronaviruses, but there is an urgent need for in-depth research on emerging human infectious coronaviruses. Clarification transmission routes and pathogenic mechanisms, and identification of potential drug treatment targets will promote the development of effective prevention and treatment measures. In the absence of confirmed effective treatments, due to public health emergencies, it is essential to study the possible effects of existing approved antivirals drugs or Chinese herbal medicines for SARS-CoV-2. This review summarizes the epidemiological characteristics, pathogenesis, virus structure and targeting strategies of COVID-19. Meanwhile, this review also focus on the re-purposing of clinically approved drugs and Chinese herbal medicines that may be used to treat COVID-19 and provide new ideas for the discovery of small molecular compounds with potential therapeutic effects on novel COVID-19.
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Project description:The outbreak of novel coronavirus strain (Covid-19) with a high pandemic threat has predict grave public health and economic concerns. This virus, originating from the Wuhan region in China has spread worldwide affecting millions with no registered persuasive targeted therapy. In this paper, we analyze the three important proteins encoded by the virus, envelope protein 5 × 29, RNA binding nucleocapsid protein 1SSK, and spike glycoprotein 6ACD, for an effective virion accumulation, and remdesivir was the first drug approved by the FDA and EMA for the treatment of COVID-19 cases that require hospitalization, there is still much controversy about its efficacy and also an alternative for novel phytochemicals, deoxynojirimycin, trigoneoside IB, and octanoic acid. The in-silico evaluations were conducted using the PyRx virtual screening tools which lead to the target based on high binding affinity. Trigoneoside IB, derived from Trigonella foenum-graecum (Fenugreek), showed the highest binding affinity and stable interaction with the amino acid residues present in active sites of Covid-19 proteins. Meanwhile, the other two compounds derived from Morus alba (Mulberry) and Morinda citrifolia (Noni), as well as the anti-HIV remdesivir drug exhibited good binding affinity and favorable ADME properties. Thereby offering scope for validation of the new therapeutic components for their in vitro and in vivo efficacy against the Covid-19 proteins.
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Project description:tRNase ZL-utilizing efficacious gene silencing (TRUE gene silencing) is an RNA-mediated gene expression control technology that has therapeutic potential. This technology is based on the properties of tRNase ZL that it can cleave any target RNA at any desired site under the direction of an appropriate artificial small guide RNA (sgRNA) and that cytosolic tRNase ZL can modulate gene expression by cleaving mRNA under the direction of cellular 5M-bM-^@M-2-half-tRNA or microRNA as sgRNA. In order to estimate a number of potential therapeutic heptamer-type sgRNAs for hematological malignancies, we constructed an sgRNA library composed of 156 heptamer-type sgRNAs, and examined how the sgRNAs affect viability of leukemia and myeloma cells. And we found that 20 of the 156 sgRNAs can efficiently induce apoptosis in at least one of the cancer cell lines. Furthermore, we demonstrated that 4 of the 20 effective sgRNAs can reduce growth rates of HL60 cells in mouse xenograft models. DNA microarray analysis for changes in an mRNA profile by these four heptamer-type sgRNAs suggested at least one candidate target mRNA that contains a potential tRNase ZL target site for each sgRNA. Changes in gene expression in HL60 cells were measured after 18-hour incubation in the absence or presence of one of five different heptamer-type sgRNAs. *Heptamer sequences requested but not provided by submitter
2014-06-30 | E-GEOD-49578 | biostudies-arrayexpress
Project description:Coronavirus desease 2019 (COVID-19) is responsible for more than 1.80 M deaths worldwide. A Quantitative Structure-Activity Relationships (QSAR) model is developed based on experimental pIC50 values reported for a structurally diverse dataset. A robust model with only five descriptors is found, with values of R2 = 0.897, Q2LOO = 0.854, and Q2ext = 0.876 and complying with all the parameters established in the validation Tropsha's test. The analysis of the applicability domain (AD) reveals coverage of about 90% for the external test set. Docking and molecular dynamic analysis are performed on the three most relevant biological targets for SARS-CoV-2: main protease, papain-like protease, and RNA-dependent RNA polymerase. A screening of the DrugBank database is executed, predicting the pIC50 value of 6664 drugs, which are IN the AD of the model (coverage = 79%). Fifty-seven possible potent anti-COVID-19 candidates with pIC50 values > 6.6 are identified, and based on a pharmacophore modelling analysis, four compounds of this set can be suggested as potent candidates to be potential inhibitors of SARS-CoV-2. Finally, the biological activity of the compounds was related to the frontier molecular orbitals shapes.
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Project description:MicroRNAs (miRNAs or miRs) contribute to the development of various malignant neoplasms, including glioblastoma multiforme (GBM). The present study aimed to explore the pathogenesis of GBM and to identify latent therapeutic agents for patients with GBM, based on an in silico analysis. Gene chips that provide miRNA expression profiling in GBM were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed miRNAs (DEMs) were also determined via the RobustRankAggreg algorithm. The target genes of DEMs were predicted and then intersected with GBM?associated genes that were collected from the Gene Expression Profiling Interactive Analysis. Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the overlapping genes were then performed. Simultaneously, a connectivity map (CMap) analysis was performed to screen for potential therapeutic agents for GBM. A total of 10 DEMs (hsa?miR?196a, hsa?miR?10b, hsa?miR?196b, hsa?miR?18b, hsa?miR?542?3p, hsa?miR?129?3p, hsa?miR?1224?5p, hsa?miR?876?3p and hsa?miR?770?5p) were obtained from three GEO gene chips (GSE25631, GSE42657 and GSE61710). Then, 1,720 target genes of the 10 miRNAs and 4,185 differently expressed genes in GBM were collected. By intersecting the aforementioned gene clusters, the present study identified 390 overlapping genes. GO and KEGG analyses of the 390 genes demonstrated that these genes were involved in certain cancer?associated biological functions and pathways. Eight genes [(GTPase NRas (NRAS), calcium/calmodulin?dependent protein kinase type II subunit Gamma (CAMK2G), platelet?derived growth factor receptor alpha (PDGFRA), calmodulin 3 (CALM3), cyclin?dependent kinase 6 (CDK6), calcium/calmodulin?dependent protein kinase type II subunit beta (CAMK2B), retinoblastoma?associated protein (RB1) and protein kinase C beta type (PRKCB)] that were centralized in the glioma pathway were selected for CMap analysis. Three chemicals (W?13, gefitinib and exemestane) were identified as putative therapeutic agents for GBM. In summary, the present study identified three miRNA?based chemicals for use as a therapy for GBM. However, more experimental data are needed to verify the therapeutic properties of these latent drugs in GBM.
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| S-EPMC9245396 | biostudies-literature
Project description:A new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a respiratory infection out broke in December 2019 in Wuhan, Hubei province, China, resulted in pandemic conditions worldwide. COVID-19 spread swiftly around the world over with an alert of an emergency for an adequate drug. Therefore, in this research, we repurposed the FDA-approved medicines to find the prominent drug used to cure the COVID infected patients. We performed homology modeling of the transmembrane serine protease 2 (TMPRSS2), responsible for the viral entry. The prediction of the transmembrane region and the Conserved Domain in TMPRSS2 protein was made for docking. 4182 FDA-approved compounds from the ZINC database were downloaded and used for the calculation of physicochemical properties. Two thousand eight hundred fifteen screened compounds were used for molecular docking against the modelled protein structure. From which top hit compounds based on binding energy were extracted. At 1st site pose, ZINC3830554 showed the highest binding energy -12.91kcal/mol by forming Salt Bridge at LYS143, Hydrogen bond at ALA8, VAL45, HIS47, SER142, ASN277, ASN359, and TRP363. The hydrophobic Interactions at PHE3, LEU4, ALA7, ALA8, ALA139, PRO197, and PHE266. In the 2nd site pose, ZINC203686879 shows the highest binding energy (-12.56 kcal/mol) and forms a hydrophobic interaction with VAL187, VAL189, HIS205, LYS301, GLN347, TRP370 and hydrogen bond was at GLY300, THR302, GLN347, SER350 residues. These hit compounds were subjected to stability checks between the protein-ligand complex through the dynamics simulation (MD), and binding free energy was calculated through the Molecular Mechanics energies combined with Poisson-Boltzmann (MM/PBSA) method. We hope that hit compounds would be an efficient inhibitor that can block the TMPRSS2 activity and resist the entry of the SARS-CoV-2 virus into targeted human cells by reducing the virus's infectivity and transmissibility.
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