In silico Evaluation of Guaiane Sesquiterpenes as Multi-Target Inhibitors of Key Proteins in Breast Cancer

Abstract

Breast cancer is one of the most prevalent cancers among women worldwide, and despite advancements in treatment, the current therapeutic options often come with severe side effects and the risk of drug resistance. This highlights the need for identifying new compounds with better efficacy and safety profiles. In this study, twenty guaiane sesquiterpenes were investigated for their potential as inhibitors of key proteins associated with breast cancer progression, including Progesterone Receptor (PR), Epidermal Growth Factor Receptor (EGFR), p53 Inducible Ribonucleotide Reductase (P53R2), Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4), and Cyclin-Dependent Kinase 8 (CDK8).The compounds were first evaluated for drug-likeness using the SwissADME web server based on Lipinski’s Rule of Five, followed by molecular docking to determine their binding affinities with each target protein. The binding energies of the compounds were compared with those of standard breast cancer drugs to assess their inhibitory potentials. Bioavailability and toxicity predictions were also conducted using the SwissADME and ADMETlab 2.0 web servers, respectively. All the compounds met Lipinski’s criteria for drug-likeness. Five compounds (4, 8, 13, 16, and 20) demonstrated superior or comparable binding affinities to standard drugs across the five target proteins, suggesting their potential as lead candidates. Further analysis indicated that these compounds have favorable bioavailability profiles; however, one of them (Compound 8) exhibited a potential risk of carcinogenicity. In conclusion, the findings suggest that guaiane sesquiterpenes hold promise as a source of novel lead compounds for the treatment of breast cancer, with a need for further in vitro and in vivo studies to validate their efficacy and safety. This study contributes to the ongoing search for more effective and safer therapeutic options for breast cancer management