Abstract
Novel SARS-CoV-2, an etiological factor of Coronavirus disease 2019 (COVID-19), poses a great challenge to the public health care system. Among other druggable targets of SARS-Cov-2, the ...main protease (M
pro
) is regarded as a prominent enzyme target for drug developments owing to its crucial role in virus replication and transcription. We pursued a computational investigation to identify M
pro
inhibitors from a compiled library of natural compounds with proven antiviral activities using a hierarchical workflow of molecular docking, ADMET assessment, dynamic simulations and binding free-energy calculations. Five natural compounds, Withanosides V and VI, Racemosides A and B, and Shatavarin IX, obtained better binding affinity and attained stable interactions with M
pro
key pocket residues. These intermolecular key interactions were also retained profoundly in the simulation trajectory of 100 ns time scale indicating tight receptor binding. Free energy calculations prioritized Withanosides V and VI as the top candidates that can act as effective SARS-CoV-2 M
pro
inhibitors.
The fundamental role of microRNAs (miRNAs) has long been associated with regulation of gene expression during transcription and post transcription of mRNA's 3′UTR by the RNA interference mechanism. ...Also, the process of how miRNAs tend to induce mRNA degradation has been predominantly studied in many infectious diseases. In this article, we would like to discuss the interaction of dietary plant miRNAs derived from fresh fruits against the viral genome of the causative agent of COVID-19, specifically targeting the 3′UTR of SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) genome. Expanding the analysis, we have also identified plant miRNAs that interact against the Omicron (B.1.1.529) variant of SARS-CoV-2 across 37 countries/territories throughout the world. This cross-species virus-plant interaction led us to identify the alignment of dietary plant miRNAs found in fruits like Citrus sinensis (Orange), Prunus persica (Peaches), Vitis vinifera (Grapes) and Malus domestica (Apple) onto the viral genomes. In particular, the interaction of C. sinensis miRNA - csi-miR169–3p and SARS-CoV-2 is noteworthy, as the targeted 3′UTR region “CTGCCT” is found conserved amongst all curated 772 Omicron variants across the globe. Hence this site “CTGCCT” and miRNA csi-miR169–3p may become promising therapeutic candidates to induce viral genome silencing. Thereby, this study reveals the mechanistic way of how fruits tend to enact a fight against viruses like SARS-CoV-2 and aid in maintaining a strong immune system of an individual.
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•Exploring cross-species interaction amongst dietary plant miRNAs and SARS-CoV-2.•Sequence conservation analysis between 3′ UTR of Reference and Omicron variants of SARS-CoV-2 genomes.•Unravelling the interaction between Citrus sinensis miR169–3p and conserved “CTGCCT” site in all curated 770 Omicron variants.•Discussing miRNAs' plausible mode of action to induce immunomodulatory response.
Understanding how MHC class II (MHC‐II) binding peptides with differing lengths exhibit specific interaction at the core and extended sites within the large MHC‐II pocket is a very important aspect ...of immunological research for designing peptides. Certain efforts were made to generate peptide conformations amenable for MHC‐II binding and calculate the binding energy of such complex formation but not directed toward developing a relationship between the peptide conformation in MHC‐II structures and the binding affinity (BA) (IC50). We present here a machine‐learning approach to calculate the BA of the peptides within the MHC‐II pocket for HLA‐DRA1, HLA‐DRB1, HLA‐DP, and HLA‐DQ allotypes. Instead of generating ensembles of peptide conformations conventionally, the biased mode of conformations was created by considering the peptides in the crystal structures of pMHC‐II complexes as the templates, followed by site‐directed peptide docking. The structural interaction fingerprints generated from such docked pMHC‐II structures along with the Moran autocorrelation descriptors were trained using a random forest regressor specific to each MHC‐II peptide lengths (9–19). The entire workflow is automated using Linux shell and Perl scripts to promote the utilization of MHC2AffyPred program to any characterized MHC‐II allotypes and is made for free access at https://github.com/SiddhiJani/MHC2AffyPred. The MHC2AffyPred attained better performance (correlation coefficient CC of .612–.898) than MHCII3D (.03–.594) and NetMHCIIpan‐3.2 (.289–.692) programs in the HLA‐DRA1, HLA‐DRB1 types. Similarly, the MHC2AffyPred program achieved CC between .91 and .98 for HLA‐DP and HLA‐DQ peptides (13‐mer to 17‐mer). Further, a case study on MHC‐II binding 15‐mer peptides of severe acute respiratory syndrome coronavirus‐2 showed very close competency in computing the IC50 values compared to the sequence‐based NetMHCIIpan v3.2 and v4.0 programs with a correlation of .998 and .570, respectively.
MicroRNAs (miRNAs) are conserved small non coding RNAs, which are typically 22–24 nucleotides long and play an important role in post transcription regulation andin various biological processes in ...both animals and plants. Ocimum basilicum is an important medicinal plant having different bioactive compounds eugenol and essential oils that possess numerous therapeutic properties. However, only a few miRNAs of
Ocimum basilicum
and its function have been studied till date. The present study focusses on the identification of miRNA from expressed sequenced tags by carrying out computational approaches based on the homology search method. A total of 10 potential miRNAs with 8 different families were predicted in
O.basilicum
. Furthermore, the psRNA target server was used to predict cross kingdom target genes on human transcriptome for identification ofpotential miRNAs. Eight miRNA families were found to modulate the 87 human target genes which were associated with RAS/MAPK signalling cascade, cardiomyopathy, HIV, breast cancer, lung cancer, Alzheimer’s diseases and several neurological disorders. Moreover,
O.basilicum
miRNAs regulate the key human target genes having significance in various diseases and important biological networks with 10 hub nodes interactions. Thus this study gives the pave for further studies to explore the potential of miRNA mediated cross kingdom regulation and treatment of various diseases including cancer.
Computational methods have driven the rapid identification of tobacco microRNAs (miRNAs) from tissue-specific sequence data and witnessed success in associating miRNAs in response to stress, ...pollutants, viral infection and resistance, and cigarette smoking. Although tobacco exerted medicinal properties through phytochemicals, the role of its miRNAs in regulating tobacco and human genes and related functional implications is not elucidated thoroughly. In this present study, we have identified new and homologous miRNAs using a rigorous workflow of miRNA derivation and target prediction upon a comprehensive collection of tobacco expressed sequence tags and charted its putative roles in gene regulation via inter and intraspecies relationships. Current, computational approach have identified a total of 38 mature miRNAs comprising 31 tobacco-specific miRNAs from plant homologous families, and 7 new miRNA candidates. These seven new miRNAs were studied for tobacco target gene prediction in which most of them encode innate immunity, defense mechanism, plant development, F-box/Leucine rich-repeat protein and other protein kinases. Two out of these seven miRNAs have passed the updated emphasized criteria namely nta-miR403 and nta-miR8036. Interestingly, the workflow succeeded in establishing an intraspecies relationship by distinguishing the molecular targets already known in tobacco and homologous plants. Interspecies relationship between 38 tobacco miRNAs upon human transcriptome data revealed the most significant target CCDC88c (DAPLE) with perfect seed pairing of miR-156, regulating non-canonical WNT signaling pathways in cancer progression and metastasis. These findings may add to existing knowledge of impacting canonical WNT/β-catenin pathways. These decisive findings hold a strong clue for promoting tobacco miRNAs research and outlined the prediction of conserved miRNAs and their functions in inter and intraspecies relationships.
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•In-silico identification of 31 known and 7 new miRNAs in Nicotiana tabacum (N. tabacum).•Revealed the 7 new miRNAs’ plant specific role in immunity, defence and development.•First report of intra and interspecies relationship using N. tabacum miRNAs.•Unraveling the possible role of ‘nta-miR156 and Human CCDC88c (DAPLE) interaction’ in cancer metastasis.•Introducing two new miRNAs namely nta-miR403 and nta-miR8036 with updated emphasized criteria.
Sesame (
Sesamum indicum
L.) is an oilseed crop challenged by many biotic stresses. Charcoal rot caused by
Macrophomina phaseolina
(MP) is one of the most devastating diseases of sesame. Till date, ...molecular mechanisms of resistance to charcoal rot in sesame is not yet reported. In this study, two sesame variety GT-10 (resistant) and RT-373 (susceptible) were identified with contrasting disease incidence when infected with MP. To get the molecular insight, root samples were collected at 0, 24, 48- and 72-h post inoculation (hpi) with the pathogen and generated RNAseq data was analyzed. A total of 1153 and 1226 differentially expressed genes (DEGS) were identified in GT-10 and RT-373, respectively. During the inoculation with MP, resistant genotype showed high number DEGs at early time point of 24 hpi and when compared to late expression in susceptible genotype at 48 hpi. Distinct clusters were represented for each time period represented by cytochrome P450 83B1-like, single anchor, hypothetical protein C4D60, kirola like and heat shock proteins in the resistant genotype contributing for resistance. Analysis of differentially expressed genes, catalogued the genes involved in synthesis of pathogenesis-related (PR) proteins, MYB, WRKY, leucine zipper protein, bHLH, bZIP and NAC transcription factors, ABC transporters (B, C and G subfamily), glutathione metabolism, secondary metabolites, fatty acid biosynthesis and phytohormones like auxin, abscisic acid, ethylene and gibberellic acid. Additionally, in the resistant response we have found three unique GO terms including ATP binding, ribonucleotide binding and nucleic acid binding in molecular function category. The molecular clues generated through this work will provide an important resource of genes contributing for disease resistance and could prioritize genes for functional validation in the important oil crop.
Several studies have demonstrated potential role of plant-derived miRNAs in cross-kingdom species relationships by transferring into non-plant host cells to regulate certain host cellular functions. ...How nutrient-rich plants regulate host cellular functions, which in turn alleviate physiological and disease conditions in the host remains to be explored in detail. This computational study explores the potential targets, putative role, and functional implications of miRNAs derived from
Carica papaya
L., one of the most cultivated tropical crops in the world and a rich source of phytochemicals and enzymes, in human diet. Using the next-generation sequencing, -Illumina HiSeq2500, ~ 30 million small RNA sequence reads were generated from
C. papaya
young leaves, resulting in the identification of a total of 1798 known and 49 novel miRNAs. Selected novel
C. papaya
miRNAs were predicted to regulate certain human targets, and subsequent annotation of gene functions indicated a probable role in various biological processes and pathways, such as MAPK, WNT, and GPCR signaling pathways, and platelet activation. These presumptive target gene in humans were predominantly linked to various diseases, including cancer, diabetes, mental illness, and platelet disorder. The computational finding of this study provides insights into how
C. papaya
-derived miRNAs may regulate certain conditions of human disease and provide a new perspective on human health. However, the therapeutic potential of
C. papaya
miRNA can be further explored through experimental studies.
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