Identification of potential inhibitors of Aromatase using molecular docking simulation related Breast cancer (BC)

Abstract Introduction Breast cancer is the most prevalent malignancy among women and ranks as one of the three leading cancers worldwide, alongside lung and colorectal cancers. In ۲۰۱۲, approximately ۱.۷ million new cases were diagnosed globally, with about ۵۰۰,۰۰۰ deaths attributed to the disease. The lifetime risk of a woman developing breast cancer is estimated to be between one in eight and one in ten. Breast cancer (BC), frequently driven by estrogen or progesterone, poses a particularly severe risk in postmenopausal women. Current therapeutic strategies primarily involve two approaches: modulation of estrogen receptors (ER) via selective estrogen receptor modulators (SERMs) and inhibition of the aromatase enzyme through aromatase inhibitors (AIs). Aromatase is a key enzyme responsible for converting androgen precursors, such as testosterone, into estrogen. AIs are utilized to either block estrogen production or inhibit its action on estrogen receptors. In postmenopausal women, the risk of breast cancer is heightened due to estrogen production in peripheral tissues other than the ovaries. Aromatase, present in breast tissue, contributes to local estrogen synthesis, which can be suppressed by various steroidal and nonsteroidal aromatase inhibitors. Among the available AIs used in clinical practice, Exemestane is a notable example. Methods In this study, a molecular library was constructed using Exemestane, derived from the SWISS-SIMILARITY and DrugBank databases, which identified a total of ۲۶ molecules. Docking simulations of Aromatase with these molecules were conducted in an in-silico environment using PyRx software. The data indicated that two molecules (CIDs: ۹۰۵۱ and ۱۳۷۶۹) exhibited significant interaction with Aromatase, with a minimum ∆G of less than -۸.۳. Further analysis using Discovery Studio software revealed the interacting residues for molecule (۹۰۵۱) as chain A: CYS۴۳۷, GLU۳۰۲, ALA۴۳۸, PHE۱۴۸, ILE۱۳۲, LES۱۵۲, ALA۳۰۶, ILE۱۳۳, THR۳۱۰, ASP۳۰۹, PHE۲۲۱, LEU۴۷۷, TRP۲۲۴, SER۴۷۸, and VAL۳۷۰, and for molecule (۱۳۷۶۹) as chain A: CYS۴۳۷, GLY۴۳۹, ILE۱۳۳, ARG۱۱۵, VAL۳۷۳, MET۳۷۴, LEU۳۷۲, LEU۴۷۷, PHE۱۳۴, VAL۳۷۰, TRP۲۲۴, THR۳۱۰, and ALA۳۰۶. Result and conclusion These findings suggest that the identified molecules may serve as effective aromatase inhibitors and potentially offer therapeutic benefits for the management of breast cancer. It is recommended that future investigations assess the toxicity and efficacy of these potential inhibitors through both In-vitro and In-vivo studies.

کلیدواژه ها:

Breast cancer ، Aromatase ، Docking ، PyRx ، Discovery Studio