Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly infectious zoonotic virus first reported into the human population in September 2012 on the Arabian Peninsula. The virus causes severe and often lethal respiratory illness in humans with an unusually high fatality rate. The N-terminal domain (NTD) of receptor-binding S1 subunit of coronavirus spike (S) proteins can recognize a variety of host protein and mediates entry into human host cells. Blocking the entry by targeting the S1-NTD of the virus can facilitate the development of effective antiviral drug candidates against the pathogen. Therefore, the study has been designed to identify effective antiviral drug candidates against the MERS-CoV by targeting S1-NTD. Initially, a structure-based pharmacophore model (SBPM) to the active site (AS) cavity of the S1-NTD has been generated, followed by pharmacophore-based virtual screening of 11,295 natural compounds. Hits generated through the pharmacophore-based virtual screening have re-ranked by molecular docking and further evaluated through the ADMET properties. The compounds with the best ADME and toxicity properties have been retrieved, and a quantum mechanical (QM) based density-functional theory (DFT) has been performed to optimize the geometry of the selected compounds. Three optimized natural compounds, namely Taiwanhomoflavone B (Amb23604132), 2,3-Dihydrohinokiflavone (Amb23604659), and Sophoricoside (Amb1153724), have exhibited substantial docking energy >−9.00 kcal/mol, where analysis of frontier molecular orbital (FMO) theory found the low chemical reactivity correspondence to the bioactivity of the compounds. Molecular dynamics (MD) simulation confirmed the stability of the selected natural compound to the binding site of the protein. Additionally, molecular mechanics generalized born surface area (MM/GBSA) predicted the good value of binding free energies (ΔG bind) of the compounds to the desired protein. Convincingly, all the results support the potentiality of the selected compounds as natural antiviral candidates against the MERS-CoV S1-NTD.

Single-nucleotide polymorphisms (SNPs) play a crucial role in the genetic basis of various human diseases and have the potential to serve as valuable biomarkers for disease prediction and personalized treatment. SNPs alter the genetic sequence that produce muted gene and subsequently mutated gene encode altered amino acid residues that can produce the misfolded protein. The SRY-box transcription factor 9, also known as SOX9, is a key determinant for cell growth and has a significant impact on the development of breast cancer. The molecular mechanisms by which missense SNPs in SOX9 influence the Wnt/β-catenin signalling pathway and contribute to tumour development in SOX9 members remain poorly understood and require further elucidation. Therefore, various computational methods based on sequence and structure were employed to investigate how mutations affect the SOX9 protein. We identified 5,029 SNPs in the SOX9 gene, of which 1,158 were missense (23.03%), 494 were synonymous (9.82%), and 3,377 were intronic (67.15%). SIFT analysis predicted that nine mutations were deleterious. Seven of these missense SNPs (D85H, F154L, A158T, H165Y, K173E, D441N, and G457D) were found to be damaging, potentially harmful, effective, disease-related, and highly deleterious. A high-risk mutation D85H located within the SOX9 DNA-binding HMG box domain PF00505 suggests a potential role in disease causation. Further, molecular dynamics (MD) simulation revealed variations in RMSD and RMSF values, with higher rGyr and hydrogen bond counts in the mutant protein compared to the wild-type, indicating that the mutation might alter protein structure and stability. Finally, PCA, DCCM, and FEL analyses of SOX9 apo protein and mutated D85H provided detailed insights into primary movements, internal motions, energy landscapes, and structural flexibility. Overall, these findings highlight pathways for further investigation into how missense SNPs in the SOX9 gene modify protein structure and function, potentially aiding in strategies to mitigate the negative consequences of these mutations in humans.

Glypican-3 (GPC3), a membrane-bound heparan sulfate proteoglycan, has long been found to be dysregulated in human lung adenocarcinomas (LUADs). Nevertheless, the function, mutational profile, epigenetic regulation, co-expression profile, and clinicopathological significance of the GPC3 gene in LUAD progression are not well understood. In this study, we analyzed cancer microarray datasets from publicly available databases using bioinformatics tools to elucidate the above parameters. We observed significant downregulation of GPC3 in LUAD tissues compared to their normal counterparts, and this downregulation was associated with shorter overall survival (OS) and relapse-free survival (RFS). Nevertheless, no significant differences in the methylation pattern of GPC3 were observed between LUAD and normal tissues, although lower promoter methylation was observed in male patients. GPC3 expression was also found to correlate significantly with infiltration of B cells, CD8+, CD4+, macrophages, neutrophils, and dendritic cells in LUAD. In addition, a total of 11 missense mutations were identified in LUAD patients, and ~1.4% to 2.2% of LUAD patients had copy number amplifications in GPC3. Seventeen genes, mainly involved in dopamine receptor-mediated signaling pathways, were frequently co-expressed with GPC3. We also found 11 TFs and 7 miRNAs interacting with GPC3 and contributing to disease progression. Finally, we identified 3 potential inhibitors of GPC3 in human LUAD, namely heparitin, gemcitabine and arbutin. In conclusion, GPC3 may play an important role in the development of LUAD and could serve as a promising biomarker in LUAD.