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.