Marmesin and marmelosin interact with the heparan sulfatase-2 active site: Potential mechanism for the antitumor effect of phytochemicals from bael fruit

B.S. RAVINDRANATH; CHANDRU HEMAKUMAR1 ; DARIO C. RAMIREZ; VASIST KIRAN

Congreso; Free Radical Biology And Medicine; 2022

Human heparan sulfatase-2 (HSULF-2) is an oncoproteinoverexpressed on the surface of all types of tumor cells andits activity plays a critical role in cancer survival andprogression. Our previous studies have shown that baelfruit extract, containing marmesin and marmelosin, inhibitsthe HSULF-2 activity and kills breast tumor cells, but themechanism of these processes remains fairly known mainlybecause the HSULF-2´s 3D-structure is partially known.Herein, we aimed at providing an in silico molecularmechanism of the inhibition of human HSULF-2 byphytochemicals from bael fruit extract. Pharmacokineticsparameters of the main phytochemicals contained in thebael fruit extract, sequence-based 3D structure of humanHSULF-2, as well as the interaction of bael fruit´sphytochemicals with the enzyme active site were modeled,evaluated, and verified. Docking studies revealed marmesinand marmelosin as potential inhibitors with binding scoresof -8.5 & -7.7 Kcal/mol, these results were validated usingmolecular dynamics simulations, which exhibited higherstability of the protein-ligand complexes. Taking together,with our earlier in vitro data, our computational analysessuggest that marmesin and marmelosin interact at the activesite of HSULF-2 providing a potential mechanism for itsinhibition and consequent anti-tumor activity byphytochemicals contained in the bael fruit extract.