DFT study and docking of xanthone derivatives indicating their ability to inhibit aromatase, a crucial enzyme for the steroid biosynthesis pathway

Aromatase is a crucial enzyme in the aromatization process, which catalyzes the conversion of androgenic steroids to estrogens. Aromatase dysregulation, as well as elevated estrogen levels, have been linked to a variety of malignancies, including breast cancer. Herein, we present the results of the optimization of Xanthones employing density functional theory (DFT) using the B3LYP/6-311G+(d, p) basis set to determine their frontier molecular orbitals, Mulliken charges, and chemical reactivity descriptors. According to the DFT results, Erythrommone has the smallest HOMO-LUMO gap (3.85 Kcal/mol), as well as the greatest electrophilicity index (5.19) and basicity (4.47). Xanthones and their derivatives were docked into the active site cavity of CYP450 to examine their structure-based inhibitory effect. The docking simulation studies predicted that Erythrommone has the lowest binding energy (-7.43 Kcal/mol), which is consistent with the DFT calculations and may function as a powerful CYP450 inhibitor equivalent to its known inhibitor, Exemestane, which has a binding affinity of −8.13 Kcal/mol. The high binding affinity of Xanthones was linked to the existence of hydrogen bonds as well as various hydrophobic interactions between the ligand and the receptor's essential amino acid residues. The findings demonstrated that Xanthones are more powerful inhibitors of the Aromatase enzyme than the recognized inhibitor Exemestane.