Pharmacophoric Investigation of a Natural Product-like Class of Aromatase Inhibitors Using Molecular Modeling

Endometriosis is a condition affecting approximately 10% of reproductive-age women in which endometrial tissue is found in locations outside the uterus, often causing debilitating symptoms. Aromatase, an enzyme that also plays a key role in hormone-dependent breast cancer, is abnormally expressed in the diseased tissue and converts androgens to self-produce estrogen in the diseased tissue. Available aromatase inhibitors suffer from side effects that could be mitigated with an inhibitor based on natural products. In this work, several analogues of an isoflavanone-like scaffold, a new and underexplored scaffold for aromatase inhibition, are analyzed to map the pharmacophore and identify leads. Ligands are first docked to the active site, with docking scores in the range of -11.1 to -7.9 kcal/mol, and the top 50% are analyzed further with molecular dynamics and free energy analyses. General trends of the ligands are explored, followed by a deeper analysis of the five best-performing ligands. These ligands have root-mean-square fluctuation (RMSF) values between 0.87 and 1.77 Å and binding affinities between -35.41 and -37.24 kcal/mol, which is comparable to the control drug Letrozole (-35.80 kcal/mol). These five ligands have stable binding modes and strong binding affinities and are synthetically available. The most successful ligands have a para geometry on positions 2 and 5 of the B ring, and interactions are generally improved with nonpolar functional groups. These ligands, particularly compounds 4 and 5, provide ideal starting points for further experimental analysis of this novel scaffold, and the pharmocophore map will inform the rational design.