Marmesin and Marmelosin Interact with the Heparan Sulfatase-2 Active Site: Potential Mechanism for Phytochemicals from Bael Fruit Extract as Antitumor Therapeutics

• Published in: Oxidative medicine and cellular longevity 2023, Vol.2023, p.9982194-19
• Main Authors: Hemakumar, C., Ravindranath, B. S., Ravishankar, G. A., Ramirez, D. C., Kiran, S. V.
• Format: Article
• Language: English
• Subjects: Binding sites; Breast cancer; Catalytic Domain; Cell cycle; Disease; Drugs; Fruit; Functional foods & nutraceuticals; Genes; Glycosaminoglycans; Heparan sulfate; Humans; Ligands; Molecular Docking Simulation; Pharmacokinetics; Phytochemicals; Phytochemicals - pharmacology; Plant Extracts - pharmacology; Proteins; Sulfatases
• ISSN: 1942-0900; 1942-0994
• DOI: 10.1155/2023/9982194

Human heparan sulfatase-2 (HSULF-2) is an oncoprotein overexpressed in the surface of all types of tumor cells and its activity plays a critical role in cancer survival and progression. Our previous studies have shown that bael fruit extract, containing marmesin and marmelosin, inhibits the HSULF-2 activity and kills breast tumor cells, but the mechanism of these processes remains fairly known mainly because the HSULF-2’s 3D structure is partially known. Herein, we aimed at providing an in silico molecular mechanism of the inhibition of human HSULF-2 by phytochemicals from bael fruit extract. Pharmacokinetic parameters of the main phytochemicals contained in the bael fruit extract, sequence-based 3D structure of human HSULF-2, and the interaction of bael fruit’s phytochemicals with the enzyme active site was modeled, evaluated, and verified. Docking studies revealed marmesin and marmelosin as potential inhibitors with binding score -8.5 and -7.7 Kcal/mol; these results were validated using molecular dynamics simulations, which exhibited higher stability of the protein-ligand complexes. Taking together, with our earlier in vitro data, our computational analyses suggest that marmesin and marmelosin interact at the active site of HSULF-2 providing a potential mechanism for its inhibition and consequent antitumor activity by phytochemicals contained in the bael fruit extract.