Comparative in silico evaluation of steroidal and non-steroidal sulfamates as potential human steroid sulfatase inhibitors.

Abstract

Steroid sulfatase (STS) is a membrane-bound enzyme and a key therapeutic target for hormone-dependent disorders. This study evaluates four sulfamate-based STS inhibitors Coumate, Irosustat (STX64), STX213, and STX1938 across both the catalytic core (Site 1) and the secondary membrane-gate vestibule (Site 2) of human STS (hSTS; PDB ID: 8EG3). Molecular docking and molecular dynamics (MD) simulations were integrated with Prime MM-GBSA energetic calculations, residue contact mapping, and computational ADMET profiling. At the catalytic site, key interactions with formylglycine (FGly75), Lys368, His290, and Phe178 were maintained, though bulky steroidal frameworks experienced structural displacement. Conversely, the membrane-gate vestibule offered a hydrophobic environment that facilitated sustained ligand retention. Irosustat exhibited the most favorable trajectory-averaged MM-GBSA binding score at Site 1 (-408.6 kcal/mol), whereas Irosustat and STX1938 demonstrated comparable affinities at Site 2 (-390.4 and -389.0 kcal/mol, respectively), with STX1938 establishing particularly dense, persistent vestibule contacts. These computational findings suggest that the membrane-gate vestibule may act as a dynamically stable retention site predicted to modulate inhibitor passage into the catalytic core. Site-2 occupancy is thus proposed as a putative gatekeeper mechanism to guide future experimental validation and inhibitor design.