Repurposing FDA-Approved Anastrozole-based Drugs for Breast Cancer through Drug-Drug Transcriptomic Similarity and Cavity Detection Guided Blind Docking

Abstract

Breast cancer remains a significant global health concern, necessitating innovative strategies for drug discovery and development. Repurposing existing drugs offers a promising avenue, leveraging the wealth of information available on food and drug administration (FDA) approved compounds. This study investigates the repurposing potential of anastrozole-based drugs, already established for their efficacy in certain conditions, for breast cancer treatment. This research presents a multifaceted investigation into the identification, structural refinement, and virtual screening of potential therapeutics targeting the aromatase CYP19A enzyme, a crucial player in hormone-related conditions such as breast cancer. The study commences with the identification of anastrozole-based drugs exhibiting transcriptomic profiles closely resembling known breast cancer therapeutics. Through a comprehensive analysis, a subset of compounds demonstrates high transcriptomic similarity, suggesting shared molecular pathways and target interactions. Notably, anastrozole, a well-known aromatase inhibitor, emerges as a top candidate, highlighting its potential in breast cancer treatment. The crystallographic structure of aromatase CYP19A is subjected to meticulous preprocessing using the PDB-REDO server, resulting in significant improvements in various validation metrics. Structural changes, including alterations in rotamers, removal of water molecules, and peptide flips, indicate the success of the refinement process in enhancing the accuracy of the protein model. The refined structure serves as a reliable foundation for subsequent studies. Further, structure-based cavity detection unveils potential binding sites on the aromatase enzyme. Docking studies employing the cb-dock server elucidate the interaction patterns and binding affinities of selected compounds within these cavities. Anastrozole, along with other candidates like dolasetron and stiripentol, exhibits promising binding scores and interacts with specific residues crucial for enzyme activity. This integrative approach, combining transcriptomic similarity analysis, structural refinement, and virtual screening, provides valuable insights into potential lead compounds for the inhibition of aromatase in breast cancer therapy. The identified compounds offer a starting point for further experimental validation and drug development. The most promising compound that can be repurposed for as an aromatase inhibitor is dolasetron. Overall, this research contributes to the ongoing efforts to leverage computational methodologies for the rational design of targeted therapeutics against hormone-related disorders.