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Mitogen-activated protein kinase 1 (MAPK1) is a serine/threonine kinase that plays a crucial role in the MAP kinase signaling transduction pathway. This pathway plays a crucial role in various cellular processes, including cell proliferation, differentiation, adhesion, migration, and survival. Besides, many chemotherapeutic drugs targeting the MAPK pathway are used in clinical practice, and novel inhibitors of MAPK1 with improved specificity and efficacy are required. Hence, targeting MAPK1 can be crucial to control metastasis in cancer therapeutics. In this study, we utilized a structure-guided virtual screening approach to screen a library of thousands of natural compounds from the ZINC database. The Lipinski rule of five (RO5) was used as a criterion for the primary selection of natural compounds. The screened compounds were prioritized based on their binding affinity, docking scores, and specificity towards the kinase domain of MAPK1 during the molecular docking process. Subsequently, the selected hits underwent rigorous screening that included the identification of potential pan-assay interference compounds (PAINS), ADMET evaluation, and prediction of pharmacological activities using PASS analysis. Afterwards, we performed a comprehensive interaction analysis to explore the binding prototypes of the screened molecules with the key residues within the MAPK1 kinase domain. Finally, selected molecules underwent extensive all-atom molecular dynamics (MD) simulations for a time duration of 200 nanoseconds. The study pinpointed three natural compounds with ZINC database IDs ZINC0209285, ZINC02130647, and ZINC02133691 as potential inhibitors of MAPK1. The study highlights that these compounds could be explored further in preclinical and clinical investigations to develop anticancer therapeutics.

This study provides insight into therapy for lung cancer, establishing p-C resol ( p-C) as an inhibitor of Pyruvate Dehydrogenase Kinase 3 (PDK3). PDK3 is critical in cancer metabolism by regulating the pyruvate dehydrogenase complex, shifting cellular energy production towards glycolysis, and promoting tumor growth and survival under hypoxic conditions. In this study, we have used computational and experimental approaches. Molecular docking reveals that p-C occupies PDK3’s binding pocket and forms interactions with key residues, especially Asp 287. Molecular dynamic simulation (MD) studies showed that p-C induced minimum alterations in PDK3, suggesting the structural stability of the PDK3- p-C complex. A fluorescence-based binding study demonstrated the binding of p-C to PDK3 with a binding constant of 3.8 × 10 8 M −1 , indicating excellent binding affinity. Cell-based enzyme assay revealed significant inhibition of PDK3 by p-C , establishing it as a PDK3 inhibitor. Moreover, cellular assays also demonstrated significant inhibition of PDK3 activity and tumor progression. This study provides a promising therapeutic avenue for improving lung cancer treatment outcomes by targeting PDK3. 

Head and neck squamous cell carcinoma (HNSCC) is a prevalent malignancy with a poor prognosis, whose biomarkers have not been studied in great detail. We have collected genomic data of HNSCC patients from The Cancer Genome Atlas (TCGA) and analyzed them to get deeper insights into the gene expression pattern. Initially, 793 differentially expressed genes (DEGs) were categorized, and their enrichment analysis was performed. Later, a protein–protein interaction network for the DEGs was constructed using the STRING plugin in Cytoscape to study their interactions. A set of 10 hub genes was selected based on Maximal Clique Centrality score, and later their survival analysis was studied. The elucidated set of 10 genes, i.e., PRAME, MAGEC2, MAGEA12, LHX1, MAGEA3, CSAG1, MAGEA6, LCE6A, LCE2D, LCE2C, referred to as potential candidates to be explored as HNSCC biomarkers. The Kaplan–Meier overall survival of the selected genes suggested that the alterations in the candidate genes were linked to the decreased survival of the HNSCC patients. Altogether, the results of this study signify that the genomic alterations and differential expression of the selected genes can be explored in therapeutic interpolations of HNSCC, exploiting early diagnosis and target-propelled therapy.

The main protease (Mpro or 3CLpro or nsp5) of SARS-CoV-2 is crucial to the life cycle and pathogenesis of SARS-CoV-2, making it an attractive drug target to develop antivirals. This study employed the virtual screening of a few phytochemicals, and the resultant best compound, Scopoletin, was further investigated by a FRET-based enzymatic assay, revealing an experimental IC50 of 15.75 µM. The impact of Scopoletin on Mpro was further investigated by biophysical and MD simulation studies. Fluorescence spectroscopy identified a strong binding constant of 3.17 × 104 M⁻1 for Scopoletin binding to Mpro, as demonstrated by its effective fluorescence quenching of Mpro. Additionally, CD spectroscopy showed a significant reduction in the helical content of Mpro upon interaction with Scopoletin. The findings of thermodynamic measurements using isothermal titration calorimetry (ITC) supported the spectroscopic data, indicating a tight binding of Scopoletin to Mpro with a KA of 2.36 × 103 M−1. Similarly, interaction studies have also revealed that Scopoletin forms hydrogen bonds with the amino acids nearest to the active site, and this has been further supported by molecular dynamics simulation studies. These findings indicate that Scopoletin may be developed as a potential antiviral treatment for SARS-CoV-2 by targeting Mpro.

Mitotic regulators play an essential role in cell cycle progression by ensuring correct chromosomal alignment, segregation, DNA replication, repair, and division, thereby maintaining genomic stability. Aberrant activity of cell cycle kinases, including aurora kinase B (AURKB) and cyclin-dependent kinase 1 (CDK1), might lead to disrupted mitotic checkpoints, causing aneuploidies and uncontrolled proliferation, which are critical hallmarks of cancers. Targeted inhibition of cell cycle kinases is an attractive strategy to combat cancers with minimal side effects. This study employed a comprehensive multi-staged computational approach to discover dual-targeting inhibitors against AURKB and CDK1, which are reported as key promoters of tumorigenesis. High-throughput screening of phytochemicals available in the Indian Medicinal Plants, Phytochemistry, and Therapeutics (IMPPAT) database was conducted to identify common lead/s from top hits. Jervine (IMPHY000366), a steroid alkaloid, emerged as a common compound depicting high binding affinity and ligand efficiency for AURKB and CDK1. In addition, this compound qualified all drug-like filters. After structure analysis, the docked complex was subjected to 300 ns MD simulation studies, confirming structural integrity in AURKB and CDK1 upon binding of Jervine. H-bonding pattern, secondary structural content, free energy landscape, and principal component analysis further supported Jervine’s strong and stable affinity for AURKB and CDK1. Lastly, MMPBSA showed a higher negative free energy in the presence of Jervine than VX-680 when complexed with AURKB. Finally, our results suggest that Jervine is a potent, dual-targeting kinase inhibitor with favourable pharmacokinetic and therapeutic properties, warranting further experimental validation for anticancer drug development.

Background/Aim: Cancer remains a leading cause of mortality globally, driven by complex molecular mechanisms and characterized by significant biological heterogeneity across cancer types. We aimed to discover mitogen-activated protein kinases (MAPKs) family members as both biomarkers and therapeutic targets in different cancer types. MAPKs are key signaling molecules regulating cell proliferation, differentiation, stress response, and apoptosis. Dysregulation of MAPK pathways has been implicated in the onset and progression of multiple cancers, contributing to tumor growth, metastasis, and therapeutic resistance. Given their diverse roles across cancer types, systematic analysis of MAPK gene expression, mutations, and interactions with tumor microenvironment is essential.Materials and Methods: The present study undertakes a comprehensive transcriptomic analysis of MAPKs in nine major cancer types using RNA-Seq datasets from The Cancer Genome Atlas (TCGA). RNA-Seq data were analyzed to identify differentially expressed MAPKs across nine cancer types using DESeq2, NOIseq, and limma. Significant genes (adjusted p<0.05) were subjected to GO and KEGG enrichment (EnrichR), mutational profiling (cBioPortal), and Kaplan-Meier survival analysis. Tumor immune infiltration was further assessed using TIMER2.0 to explore immune–gene interactions.Results: Through rigorous differential expression analysis, we identified key MAPKs that are significantly altered in liver hepatocellular carcinoma (LIHC) and lung adenocarcinoma (LUAD). Specifically, six MAPKs (MAPK3, MAPK7, MAPK9, MAPK10, MAPK12, and MAPK13) were found to be differentially expressed in LIHC, while MAPK6 emerged as the sole significant candidate in LUAD. Functional enrichment and pathway analysis revealed that these MAPKs are involved in critical oncogenic pathways, including MAPK-mediated transcriptional regulation and stress-activated signaling cascades. Mutational profiling and survival analysis further validated the prognostic significance of these genes, with several MAPKs showing strong associations with reduced patient survival. Tumor immune infiltration analysis indicated potential roles of these MAPKs in modulating immune responses within the tumor microenvironment. Also, MAPKs identified in this study are structurally related, suggesting that targeting them collectively may enhance therapeutic efficacy and overcome resistance mechanisms.Conclusion: Our integrated approach underscores the value of MAPK family members as both biomarkers and therapeutic targets in LIHC and LUAD. This study contributes important insights into MAPK-related oncogenic processes and supports the development of targeted therapies under the framework of precision oncology.

The main protease (M[sup.pro] or 3CL[sup.pro] or nsp5) of SARS-CoV-2 is crucial to the life cycle and pathogenesis of SARS-CoV-2, making it an attractive drug target to develop antivirals. This study employed the virtual screening of a few phytochemicals, and the resultant best compound, Scopoletin, was further investigated by a FRET-based enzymatic assay, revealing an experimental IC[sub.50] of 15.75 µM. The impact of Scopoletin on M[sup.pro] was further investigated by biophysical and MD simulation studies. Fluorescence spectroscopy identified a strong binding constant of 3.17 × 10[sup.4] M⁻[sup.1] for Scopoletin binding to M[sup.pro] , as demonstrated by its effective fluorescence quenching of M[sup.pro] . Additionally, CD spectroscopy showed a significant reduction in the helical content of M[sup.pro] upon interaction with Scopoletin. The findings of thermodynamic measurements using isothermal titration calorimetry (ITC) supported the spectroscopic data, indicating a tight binding of Scopoletin to M[sup.pro] with a K[sub.A] of 2.36 × 10[sup.3] M[sup.−1] . Similarly, interaction studies have also revealed that Scopoletin forms hydrogen bonds with the amino acids nearest to the active site, and this has been further supported by molecular dynamics simulation studies. These findings indicate that Scopoletin may be developed as a potential antiviral treatment for SARS-CoV-2 by targeting M[sup.pro] .

The main protease (M or 3CL or nsp5) of SARS-CoV-2 is crucial to the life cycle and pathogenesis of SARS-CoV-2, making it an attractive drug target to develop antivirals. This study employed the virtual screening of a few phytochemicals, and the resultant best compound, Scopoletin, was further investigated by a FRET-based enzymatic assay, revealing an experimental IC of 15.75 µM. The impact of Scopoletin on M was further investigated by biophysical and MD simulation studies. Fluorescence spectroscopy identified a strong binding constant of 3.17 × 10 M⁻ for Scopoletin binding to M , as demonstrated by its effective fluorescence quenching of M . Additionally, CD spectroscopy showed a significant reduction in the helical content of M upon interaction with Scopoletin. The findings of thermodynamic measurements using isothermal titration calorimetry (ITC) supported the spectroscopic data, indicating a tight binding of Scopoletin to M with a K of 2.36 × 10 M . Similarly, interaction studies have also revealed that Scopoletin forms hydrogen bonds with the amino acids nearest to the active site, and this has been further supported by molecular dynamics simulation studies. These findings indicate that Scopoletin may be developed as a potential antiviral treatment for SARS-CoV-2 by targeting M .