Uncovering hub genes and screening of natural CDK1 inhibitors for targeting in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, necessitating the identification of novel therapeutic targets. In this study, we utilized microarray-based genomic analysis to identify key up regulated genes in HCC. Gene expression data from 14 datasets (Affymetrix and Illumina platforms) were retrieved from the GEO database, having 1,765 normal and tumour samples. Differential expression analysis using GEO2R searched 555 unique up regulated genes, which were subjected to functional enrichment and pathway analysis via Enrich R related to cancer progression, such as p53 signaling pathway, cell cycle regulation and apoptosis. Protein-protein interaction analysis in Cytoscape, using CytoHubba algorithms, identified Cyclin dependent kinase-1(CDK1) as the top hub gene. Molecular docking study was conducted using a library of 1,574 natural compounds from the NPACT database. The docking analysis identified top three compounds with the highest docking score and highest binding affinities to CDK1 were selected for further MD simulation analysis (500 ns) and MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) to find out the protein ligand complex stability and calculate the binding free energy of top three compounds respectively. This study findings, Isocarthamidin, luteolin, and Sonderianol target high CDK1 levels and could be useful inhibitors for patients with HCC. This integrated computational net throws up CDK1 as an important therapeutic target in HCC and comes out with three natural compounds that can be considered optimistic lead candidates. Though it still has to be validated through experiments, the findings provide testable assumptions for the development of therapies directed towards CDK1 in HCC.