Bioinformatics-based investigation on the genetic influence between SARS-CoV-2 infections and idiopathic pulmonary fibrosis (IPF) diseases, and drug repurposing.

Some recent studies showed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and idiopathic pulmonary fibrosis (IPF) disease might stimulate each other through the shared genes. Therefore, in this study, an attempt was made to explore common genomic biomarkers for SARS-CoV-2 infections and IPF disease highlighting their functions, pathways, regulators and associated drug molecules. At first, we identified 32 statistically significant common differentially expressed genes (cDEGs) between disease (SARS-CoV-2 and IPF) and control samples of RNA-Seq profiles by using a statistical r-package (edgeR). Then we detected 10 cDEGs (CXCR4, TNFAIP3, VCAM1, NLRP3, TNFAIP6, SELE, MX2, IRF4, UBD and CH25H) out of 32 as the common hub genes (cHubGs) by the protein-protein interaction (PPI) network analysis. The cHubGs regulatory network analysis detected few key TFs-proteins and miRNAs as the transcriptional and post-transcriptional regulators of cHubGs. The cDEGs-set enrichment analysis identified some crucial SARS-CoV-2 and IPF causing common molecular mechanisms including biological processes, molecular functions, cellular components and signaling pathways. Then, we suggested the cHubGs-guided top-ranked 10 candidate drug molecules (Tegobuvir, Nilotinib, Digoxin, Proscillaridin, Simeprevir, Sorafenib, Torin 2, Rapamycin, Vancomycin and Hesperidin) for the treatment against SARS-CoV-2 infections with IFP diseases as comorbidity. Finally, we investigated the resistance performance of our proposed drug molecules compare to the already published molecules, against the state-of-the-art alternatives publicly available top-ranked independent receptors by molecular docking analysis. Molecular docking results suggested that our proposed drug molecules would be more effective compare to the already published drug molecules. Thus, the findings of this study might be played a vital role for diagnosis and therapies of SARS-CoV-2 infections with IPF disease as comorbidity risk.

Identification of host genomic biomarkers from multiple transcriptomics datasets for diagnosis and therapies of SARS-CoV-2 infections.

The pandemic of COVID-19 is a severe threat to human life and the global economy. Despite the success of vaccination efforts in reducing the spread of the virus, the situation remains largely uncontrolled due to the random mutation in the RNA sequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which demands different variants of effective drugs. Disease-causing gene-mediated proteins are usually used as receptors to explore effective drug molecules. In this study, we analyzed two different RNA-Seq and one microarray gene expression profile datasets by integrating EdgeR, LIMMA, weighted gene co-expression network and robust rank aggregation approaches, which revealed SARS-CoV-2 infection causing eight hub-genes (HubGs) including HubGs; REL, AURKA, AURKB, FBXL3, OAS1, STAT4, MMP2 and IL6 as the host genomic biomarkers. Gene Ontology and pathway enrichment analyses of HubGs significantly enriched some crucial biological processes, molecular functions, cellular components and signaling pathways that are associated with the mechanisms of SARS-CoV-2 infections. Regulatory network analysis identified top-ranked 5 TFs (SRF, PBX1, MEIS1, ESR1 and MYC) and 5 miRNAs (hsa-miR-106b-5p, hsa-miR-20b-5p, hsa-miR-93-5p, hsa-miR-106a-5p and hsa-miR-20a-5p) as the key transcriptional and post-transcriptional regulators of HubGs. Then, we conducted a molecular docking analysis to determine potential drug candidates that could interact with HubGs-mediated receptors. This analysis resulted in the identification of top-ranked ten drug agents, including Nilotinib, Tegobuvir, Digoxin, Proscillaridin, Olysio, Simeprevir, Hesperidin, Oleanolic Acid, Naltrindole and Danoprevir. Finally, we investigated the binding stability of the top-ranked three drug molecules Nilotinib, Tegobuvir and Proscillaridin with the three top-ranked proposed receptors (AURKA, AURKB, OAS1) by using 100 ns MD-based MM-PBSA simulations and observed their stable performance. Therefore, the findings of this study might be useful resources for diagnosis and therapies of SARS-CoV-2 infections.

Meta-Data Analysis to Explore the Hub of the Hub-Genes That Influence SARS-CoV-2 Infections Highlighting Their Pathogenetic Processes and Drugs Repurposing.

The pandemic of SARS-CoV-2 infections is a severe threat to human life and the world economic condition. Although vaccination has reduced the outspread, but still the situation is not under control because of the instability of RNA sequence patterns of SARS-CoV-2, which requires effective drugs. Several studies have suggested that the SARS-CoV-2 infection causing hub differentially expressed genes (Hub-DEGs). However, we observed that there was not any common hub gene (Hub-DEGs) in our analyses. Therefore, it may be difficult to take a common treatment plan against SARS-CoV-2 infections globally. The goal of this study was to examine if more representative Hub-DEGs from published studies by means of hub of Hub-DEGs (hHub-DEGs) and associated potential candidate drugs. In this study, we reviewed 41 articles on transcriptomic data analysis of SARS-CoV-2 and found 370 unique hub genes or studied genes in total. Then, we selected 14 more representative Hub-DEGs (AKT1, APP, CXCL8, EGFR, IL6, INS, JUN, MAPK1, STAT3, TNF, TP53, UBA52, UBC, VEGFA) as hHub-DEGs by their protein-protein interaction analysis. Their associated biological functional processes, transcriptional, and post-transcriptional regulatory factors. Then we detected hHub-DEGs guided top-ranked nine candidate drug agents (Digoxin, Avermectin, Simeprevir, Nelfinavir Mesylate, Proscillaridin, Linifanib, Withaferin, Amuvatinib, Atazanavir) by molecular docking and cross-validation for treatment of SARS-CoV-2 infections. Therefore, the findings of this study could be useful in formulating a common treatment plan against SARS-CoV-2 infections globally.

Identification of host transcriptome-guided repurposable drugs for SARS-CoV-1 infections and their validation with SARS-CoV-2 infections by using the integrated bioinformatics approaches.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is one of the most severe global pandemic due to its high pathogenicity and death rate starting from the end of 2019. Though there are some vaccines available against SAER-CoV-2 infections, we are worried about their effectiveness, due to its unstable sequence patterns. Therefore, beside vaccines, globally effective supporting drugs are also required for the treatment against SARS-CoV-2 infection. To explore commonly effective repurposable drugs for the treatment against different variants of coronavirus infections, in this article, an attempt was made to explore host genomic biomarkers guided repurposable drugs for SARS-CoV-1 infections and their validation with SARS-CoV-2 infections by using the integrated bioinformatics approaches. At first, we identified 138 differentially expressed genes (DEGs) between SARS-CoV-1 infected and control samples by analyzing high throughput gene-expression profiles to select drug target key receptors. Then we identified top-ranked 11 key DEGs (SMAD4, GSK3B, SIRT1, ATM, RIPK1, PRKACB, MED17, CCT2, BIRC3, ETS1 and TXN) as hub genes (HubGs) by protein-protein interaction (PPI) network analysis of DEGs highlighting their functions, pathways, regulators and linkage with other disease risks that may influence SARS-CoV-1 infections. The DEGs-set enrichment analysis significantly detected some crucial biological processes (immune response, regulation of angiogenesis, apoptotic process, cytokine production and programmed cell death, response to hypoxia and oxidative stress), molecular functions (transcription factor binding and oxidoreductase activity) and pathways (transcriptional mis-regulation in cancer, pathways in cancer, chemokine signaling pathway) that are associated with SARS-CoV-1 infections as well as SARS-CoV-2 infections by involving HubGs. The gene regulatory network (GRN) analysis detected some transcription factors (FOXC1, GATA2, YY1, FOXL1, TP53 and SRF) and micro-RNAs (hsa-mir-92a-3p, hsa-mir-155-5p, hsa-mir-106b-5p, hsa-mir-34a-5p and hsa-mir-19b-3p) as the key transcriptional and post- transcriptional regulators of HubGs, respectively. We also detected some chemicals (Valproic Acid, Cyclosporine, Copper Sulfate and arsenic trioxide) that may regulates HubGs. The disease-HubGs interaction analysis showed that our predicted HubGs are also associated with several other diseases including different types of lung diseases. Then we considered 11 HubGs mediated proteins and their regulatory 6 key TFs proteins as the drug target proteins (receptors) and performed their docking analysis with the SARS-CoV-2 3CL protease-guided top listed 90 anti-viral drugs out of 3410. We found Rapamycin, Tacrolimus, Torin-2, Radotinib, Danoprevir, Ivermectin and Daclatasvir as the top-ranked 7 candidate-drugs with respect to our proposed target proteins for the treatment against SARS-CoV-1 infections. Then, we validated these 7 candidate-drugs against the already published top-ranked 11 target proteins associated with SARS-CoV-2 infections by molecular docking simulation and found their significant binding affinity scores with our proposed candidate-drugs. Finally, we validated all of our findings by the literature review. Therefore, the proposed candidate-drugs might play a vital role for the treatment against different variants of SARS-CoV-2 infections with comorbidities, since the proposed HubGs are also associated with several comorbidities.

Computational identification of host genomic biomarkers highlighting their functions, pathways and regulators that influence SARS-CoV-2 infections and drug repurposing.

The pandemic threat of COVID-19 has severely destroyed human life as well as the economy around the world. Although, the vaccination has reduced the outspread, but people are still suffering due to the unstable RNA sequence patterns of SARS-CoV-2 which demands supplementary drugs. To explore novel drug target proteins, in this study, a transcriptomics RNA-Seq data generated from SARS-CoV-2 infection and control samples were analyzed. We identified 109 differentially expressed genes (DEGs) that were utilized to identify 10 hub-genes/proteins (TLR2, USP53, GUCY1A2, SNRPD2, NEDD9, IGF2, CXCL2, KLF6, PAG1 and ZFP36) by the protein-protein interaction (PPI) network analysis. The GO functional and KEGG pathway enrichment analyses of hub-DEGs revealed some important functions and signaling pathways that are significantly associated with SARS-CoV-2 infections. The interaction network analysis identified 5 TFs proteins and 6 miRNAs as the key regulators of hub-DEGs. Considering 10 hub-proteins and 5 key TFs-proteins as drug target receptors, we performed their docking analysis with the SARS-CoV-2 3CL protease-guided top listed 90 FDA approved drugs. We found Torin-2, Rapamycin, Radotinib, Ivermectin, Thiostrepton, Tacrolimus and Daclatasvir as the top ranked seven candidate drugs. We investigated their resistance performance against the already published COVID-19 causing top-ranked 11 independent and 8 protonated receptor proteins by molecular docking analysis and found their strong binding affinities, which indicates that the proposed drugs are effective against the state-of-the-arts alternatives independent receptor proteins also. Finally, we investigated the stability of top three drugs (Torin-2, Rapamycin and Radotinib) by using 100 ns MD-based MM-PBSA simulations with the two top-ranked proposed receptors (TLR2, USP53) and independent receptors (IRF7, STAT1), and observed their stable performance. Therefore, the proposed drugs might play a vital role for the treatment against different variants of SARS-CoV-2 infections.