New Drug Analogues as Aromatase Inhibitors: A Perspective from High-Throughput Docking and Molecular Dynamics Simulations

Breast cancer is a leading cause of cancer-related mortality. The proliferation of breast cancer cells is linked to estrogen. The aromatase enzyme plays a crucial role in the biosynthetic conversion of androgen to estrogen. Aromatase facilitates the proliferation of hormone-receptor-positive breast cancer cells. Targeting aromatase is a significant treatment approach for breast cancer. Despite the efficacy of prevalent aromatase inhibitors (AIs) such as exemestane, anastrozole and letrozole, alternate signaling pathways and mutations in the estrogen receptor gene are triggered by medication resistance. This paper aims to develop small molecules that may block aromatase with better affinity than the existing medications. To achieve this objective, prevalent AIs and an extensive array of structural analogues (1.3 × 10 6 compounds) underwent an automated high-throughput computational analysis through in silico filtration, docking and molecular dynamic (MD) simulations. Sequential filtration resulted in the selection of a nonsteroidal small molecule with PubChem compound identifier (PubChem CID 92217720) as the most promising pharmacological analogue for further development in the treatment of breast cancer. While additional advancements are expected from experimental improvements, automated approaches would facilitate the rapid screening of extensive chemical datasets with regard to the biological or pharmacological contexts.