From Docking and Molecular Dynamics to Experimental Discovery: Exploring the Hydrophobic Landscapes of Heparanase to Design Potent Inhibitors.

ABSTRACT: Heparanase (HPSE), a glycoside hydrolase that cleaves heparan sulfate chains, plays a crucial role in cancer progression by remodeling the extracellular matrix and facilitating tumor metastasis. This study employed a computational design approach to develop novel HPSE inhibitors using aminoglycoside paromomycin and neomycin analogs. These analogs feature a defined N-sulfation sequence combined with either charged or hydrophobic groups. Initial docking screenings indicated that hydrophobic-capped ligands exhibit binding energies comparable to the free hydroxyl ligands, despite displaying lower overall binding efficiencies. Molecular dynamics simulations revealed that these hydrophobic-capped ligands adopt a folded conformation, with the saccharide moiety anchored in the enzyme's acti

SUBMITTER: Abdulsalam H 

PROVIDER: S-EPMC12379015 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature