ABSTRACT
Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) Main protease (Mpro) is one of the vital drug targets amongst all the coronaviruses, as the protein is indispensable for virus replication. The study aimed to identify promising lead molecules against Mpro enzyme through virtual screening of Malaria Venture (MMV) Malaria Box (MB) comprising of 400 experimentally proven compounds. The binding affinities were studied using virtual screening based molecular docking, which revealed five molecules having the highest affinity scores compared to the reference molecules. Utilizing the established 3D structure of Mpro the binding affinity conformations of the docked complexes were studied by Molecular Dynamics (MD) simulations. The MD simulation trajectories were analysed to monitor protein deviation, relative fluctuation, atomic gyration, compactness covariance, residue-residue map and free energy landscapes. Based on the present study outcome, we propose three Malaria_box (MB) compounds, namely, MB_241, MB_250 and MB_266 to be the best lead compounds against Mpro activity. The compounds may be evaluated for their inhibitory activities using experimental techniques.
Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/pharmacology , SARS-CoV-2 , Antiviral Agents/therapeutic use , Coronavirus 3C Proteases/metabolism , Databases, Factual , Drug Discovery , Humans , Malaria/drug therapy , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/therapeutic use , COVID-19 Drug TreatmentABSTRACT
The identification of host-miRNAs targeting mutated virus genes is crucial to understand the miRNA mediated host-defense mechanism in virus infections. To understand the mechanism in COVID-19 infections, we collected genome sequences of SARS-CoV-2 with its metadata from the GISAID database (submitted till April 2020) and identified mutational changes in the sequences. The dataset consists of genes with mutation event count and entropy scores. We predicted host-miRNAs targeting the genes in the genomes and compared it with that in related viral species. We have identified 2284 miRNAs targeting MERS genomes, 2074 miRNAs targeting SARS genomes, and 1599 miRNAs targeting SARS-CoV-2 genomes, identified using the miRNA target prediction software miRanda. The host miRNAs targeting SARS-CoV-2 genes were further validated to be anti-viral miRNAs and their role in respiratory diseases through a literature survey, which helped in the identification of 42 conserved antiviral miRNAs. The data could be used to validate the anti-viral role of the predicted miRNAs and design miRNA-based therapeutics against SARS-CoV-2.
ABSTRACT
We have performed an integrative analysis of SARS-CoV-2 genome sequences from different countries. Apart from mutational analysis, we have predicted host antiviral miRNAs targeting virus genes, PTMs in the virus proteins and antiviral peptides. A comparison of the analyses with other coronavirus genomes has been performed, wherever possible. Our analysis confirms unique features in the SARS-CoV-2 genomes absent in other evolutionarily related coronavirus family genomes, which presumably confer unique infection, transmission and virulence capabilities to the virus. For understanding the crucial factors involved in host-virus interactions, we have performed Bioinformatics aided analysis integrated with experimental data related to other corona viruses. We have identified 42 conserved miRNAs that can potentially target SARS-CoV-2 genomes. Interestingly, out of these, 3 are previously reported to exhibit antiviral activity against other respiratory viruses. Gene expression analysis of known host antiviral factors reveals significant over-expression of IFITM3 and down regulation of cathepsins during SARS-CoV-2 infection, suggesting its active role in pathogenesis and delayed immune response. We also predicted antiviral peptides which can be used in designing peptide based drugs against SARS-CoV-2. Our analysis explores the functional impact of the virus mutations on its proteins and interaction of its genes with host antiviral mechanisms.