Xanthorrhizol derivatives as hyaluronidase inhibitors: In silico fragment-based drug design, in vitro evaluation and molecular dynamics simulations

Tengku Nazmi, Tengku Kamilah and Aminudin, Nurul Iman and Md Pisar, Mazura and Mohd Hashim, Siti Nur Aisyah and Hamzah, Nurasyikin and Abd Halim, Khairul Bariyyah (2026) Xanthorrhizol derivatives as hyaluronidase inhibitors: In silico fragment-based drug design, in vitro evaluation and molecular dynamics simulations. Journal of Molecular Structure, 1349. pp. 1-11. ISSN 0022-2860 E-ISSN 1872-8014

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Abstract

In this study, the anti-inflammatory potential of xanthorrhizol (XNT), a natural compound isolated from Curcuma xanthorrhiza, was enhanced through structural optimisation using in silico fragment-based drug design (FBDD) and molecular docking, targeting the hyaluronidase enzyme. The design process yielded five XNT derivatives: one known compound (2) and four novel derivatives (3–6). Derivative (3) exhibited the most favourable druglikeness property and showed the most potent activity (IC₅₀ = 44.54 µg/mL) markedly lower than XNT (1) (IC₅₀ = 203.56 µg/mL). Furthermore, molecular dynamics simulation revealed that derivative (3) maintained a stable interaction within the hyaluronidase binding pocket with key amino acid residues, with a favourable binding free energy of − 26.95 kcal/mol as calculated by the Molecular Mechanics/Generalized Born Surface Area (MM/ GBSA) method. These findings suggest that derivative (3) holds a promise as hyaluronidase inhibitor and potentially to be further developed as anti-inflammatory agent.

Item Type:	Article (Journal)
Uncontrolled Keywords:	Xanthorrhizol Fragment-based drug design Hyaluronidase Optimisation Molecular dynamics ADME
Subjects:	Q Science > Q Science (General) Q Science > QD Chemistry
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button):	Kulliyyah of Science > Department of Chemistry Kulliyyah of Science Kulliyyah of Science > Department of Biotechnology
Depositing User:	Dr Khairul Bariyyah Abd Halim
Date Deposited:	21 Oct 2025 12:00
Last Modified:	21 Oct 2025 12:00
URI:	http://irep.iium.edu.my/id/eprint/123804

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