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PC-26

Combining computational profiling and isolation of zoanthamine alkaloids

from Zoanthus sp.: A promising strategy for targeting DKK1 and GSK-3β in

osteoporosis therapy

1
1
#,1
Ngoc-Thac Pham, Bo-Rong Peng, 1,2,3 Huong-Giang Le, Lo-Yun Chen, Mei-Hsien
4
Lee, Kuei-Hung Lai* ,1,2,5

1 PhD Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy,
Taipei Medical University, Taipei 110301, Taiwan
2 Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University,
Taipei 110301, Taiwan
3 Graduate Institute of Healthy Industry Technology, Center for Drug Research and
Development, College of Human Ecology, Chang Gung University of Science and
Technology, Taoyuan 333324, Taiwan
4 Center for Reproductive Medicine and Sciences, Taipei Medical University Hospital, Taipei
110301, Taiwan
5 Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei
110301, Taiwan
* E-mail: kueihunglai@tmu.edu.tw

Abstract
Marine invertebrates from the genus Zoanthus are notable for producing a variety of
biologically active secondary metabolites with significant pharmaceutical potential. Among
these, zoanthamines - a class of alkaloids - are particularly promising for treating health
conditions like osteoporosis, a disease marked by decreased bone density and higher fracture
risk. This condition is closely linked to disruptions in the Wnt signaling pathway, crucial for
bone health and cellular processes. Targeting pathway regulators like DKK1 and GSK-3β offers
a strategic approach for developing osteoporosis treatments. This study employed an integrative
computational approach to examine zoanthamine alkaloids as potential inhibitors of DKK1 and
GSK-3β. 69 derivatives were assessed through molecular docking to predict their binding
affinities. Molecular dynamics simulations provided insights into the stability and dynamics of
protein-ligand interactions, focusing on parameters such as RMSD, RMSF, and radius of
gyration. The MM-PBSA method, combined with interaction entropy, identified promising
candidates. Zoanthus kuroshio extracts exhibited significant in vitro anti-osteoporotic activity,
leading to the isolation and characterization of five new zoanthamine alkaloids. Notably, 3-
hydroxynorzoanthamine showed enhanced alkaline phosphatase activity and mineralization in
osteoblastic cells, demonstrating strong therapeutic potential. The study highlights the potential
of zoanthamine alkaloids in osteoporosis therapy, underscoring the value of marine natural
products as sources for drug development. Future research should focus on pharmacokinetic,
pharmacodynamic, and clinical evaluations to translate these findings into effective treatments,
fully exploiting the therapeutic potential of marine-derived compounds.

Keywords: Zoanthus sp; Molecular dynamics; Osteoporosis; Isolation; Zoanthamine alkaloids