Structure-based identification of potential inhibitors of ribosomal protein S6 kinase 1, targeting cancer therapy: a combined docking and molecular dynamics simulations approach.

Ribosomal protein S6 kinase 1 (S6K1), commonly known as P70-S6 kinase 1 (p70S6), is a key protein kinase involved in cellular signaling pathways that regulate cell growth, proliferation, and metabolism. Its significant role is reported in the PIK3/mTOR signaling pathway and is associated with various complex diseases, including diabetes, obesity, and different types of cancer. Due to its involvement in various physiological and pathological conditions, S6K1 is considered as an attractive target for drug design and discovery. One way to target S6K1 is by developing small molecule inhibitors that specifically bind to its ATP-binding site, preventing its activation and thus inhibiting downstream signaling pathways necessary for cell growth and survival. In this study, we have conducted a multitier virtual screening of a pool of natural compounds to identify potential S6K1 inhibitors. We performed molecular docking on IMPPAT 2.0 library and selected top hits based on their binding affinity, ligand efficiency, and specificity towards S6K1. The selected hits were further assessed based on different filters of drug-likeliness where two compounds (Hecogenin and Glabrene) were identified as potential leads for S6K1 inhibition. Both compounds showed appreciable affinity, ligand efficiency and specificity towards S6K1 binding pocket, drug-like properties, and stable protein-ligand complexes in molecular dynamics (MD) simulations. Finally, our study has suggested that Hecogenin and Glabrene can be potential S6K1 inhibitors which are presumably implicated in the therapeutic management of associated diseases such as diabetes, obesity, and varying types of cancer.Communicated by Ramaswamy H. Sarma.

Bioactive phytoconstituents as potent inhibitors of casein kinase-2: dual implications in cancer and COVID-19 therapeutics.

Casein kinase 2 (CK2) is a conserved serine/threonine-protein kinase involved in hematopoietic cell survival, cell cycle control, DNA repair, and other cellular processes. It plays a significant role in cancer progression and viral infection. CK2 is considered a potential drug target in cancers and COVID-19 therapy. In this study, we have performed a virtual screening of phytoconstituents from the IMPPAT database to identify some potential inhibitors of CK2. The initial filter was the physicochemical properties of the molecules following the Lipinski rule of five. Then binding affinity calculation, PAINS filter, ADMET, and PASS analyses followed by interaction analysis were carried out to discover nontoxic and better hits. Finally, two compounds, stylopine and dehydroevodiamines with appreciable affinity and specific interaction towards CK2, were identified. Their time-evolution analyses were carried out using all-atom molecular dynamics simulation, principal component analysis and free energy landscape. Altogether, we propose that stylopine and dehydroevodiamines can be further explored in in vitro and in vivo settings to develop anticancer and antiviral therapeutics.

Differential gene expression and network analysis in head and neck squamous cell carcinoma.

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.