DefinePK

Abstract

Background:  Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths globally and the sixth most common cancer, particularly in the Asia-Pacific and African regions. Liver cirrhosis, a critical precursor to HCC and liver failure, necessitates effective treatment options. Although surgical intervention is the current standard, there is a pressing need for novel therapeutics with improved efficacy and reduced side effects. This study focuses on RACK1 (Receptor for Activated C-Kinase 1), a pivotal protein in cancer progression, as a therapeutic target for HCC. Methods:  Protein structures of overexpressed genes in HCC, including RACK1, were retrieved from the Protein Data Bank (PDB). Active binding sites on RACK1 were identified for potential ligand interactions. A library of 12,000 phytochemicals was sourced from PubChem, ZINC, and MP3D databases and screened against RACK1 using the PyRx virtual screening tool. The top candidates were analyzed for pharmacokinetic properties using ADMETsar. Molecular dynamics simulations were conducted to study ligand-receptor interactions and validate the potential drug candidates. Results:  The study identified promising phytochemical compounds (Pubchem11059920, Pubchem118855584, Pubchem3086637, Pubchem442813 and Pubchem88708) capable of binding to RACK1 with high affinity. These compounds exhibited favorable ADMET properties, indicating their potential as drug candidates. Molecular dynamics simulations confirmed stable and significant interactions between the identified ligands and RACK1, supporting their inhibitory potential. Conclusion:  This research highlights RACK1 as a viable therapeutic target for HCC. The identified drug candidates demonstrate potential to inhibit RACK1 function, offering a pathway to suppress HCC progression at its early stages. These findings provide a foundation for the development of effective and targeted treatments for HCC. Keywords:  Hepatocellular carcinoma (HCC), RACK1 receptor, Phytochemical screening, Virtual screening, Molecular dynamics simulation