In Silico Design and Evaluation of Quinone Methide Oxime Derivatives as Potential Non-Covalent Steroid Sulfatase Inhibitors

Steroid sulfatase (STS) plays a crucial role in intratumoral estrogen biosynthesis and represents an attractive therapeutic target in estrogen receptor-positive breast cancer. In this study, a new series of potential STS inhibitors based on the quinone methide oxime scaffold, precisely 2-(4-hydroxyiminocyclohexa-2,5-dien-1-ylidene)-2-phenylacetonitrile framework, were designed and evaluated using an integrated in silico approach. A virtual library comprising 216 compounds (including syn/anti isomers) was screened by molecular docking against the human STS crystal structure (PDB ID: 8EG3). The binding affinities ranged from −7.077 to −9.726 kcal·mol−1; however, only the best-performing compound 45-syn showed values comparable to those of the reference ligands. The top-ranked compound (45-syn) exhibited favorable interactions within the catalytic site, including polar contacts near the FGly–Ca2+ region and extensive hydrophobic and π–π interactions in the adjacent pocket. Structure–binding relationship analysis highlighted the importance of electron-withdrawing substituents at R1 and aromatic moieties at R2 for enhanced binding. Molecular dynamics simulations confirmed the stability of ligand–STS complexes and demonstrated reduced flexibility compared to the apo form. Additionally, in silico ADMET predictions indicated generally favorable drug-like profiles for selected candidates. Overall, the results highlight computationally prioritized scaffolds that merit further synthesis and biological evaluation as potential STS inhibitors.