Structure-Based Computational Screening of Indonesian Spice-Derived Compounds Targeting the Neuropeptide Y1 Receptor
Abstract
The neuropeptide Y1 receptor (NPY1R) is a promising therapeutic target for type 2 diabetes mellitus (T2DM) due to its role in regulating appetite and insulin secretion. Indonesian spices contain diverse bioactive compounds with potential metabolic effects, yet their interaction with NPY1R remains largely unexplored. This study aimed to identify potential natural allosteric modulators of NPY1R using structure-based virtual screening and pharmacokinetic analysis. A total of 17,356 compounds from the NCBI PubChem database were pre-filtered, yielding 860 ligands for blind molecular docking. Of these, 97 showed stronger predicted binding affinities than the reference antagonist BMS-193885. Further screening based on physicochemical properties, toxicity, and ADMET parameters identified six top candidates. Among them, cis-theaspirone demonstrated the most favorable profile, including binding to an allosteric pocket (–10.0 kcal/mol; RMSD 2.658 Å), high gastrointestinal absorption, blood–brain barrier permeability, and acceptable solubility. Molecular dynamics simulations over 50 ns confirmed stable ligand–receptor interactions. Overall, cis-theaspirone emerges as a potential NPY1R modulator, highlighting the promise of Indonesian spice-derived compounds for further investigation in metabolic disease research.
Downloads
References
https://www.health.harvard.edu/staying-healthy/glp-1-diabetes-and-weight-loss-drug-side-effects-oz
empic-face-and-more
Cordero, A. M. F., & Gonzales, A. A. (2024). Using Multiscale Molecular Modeling to Analyze Possible
NS2b-NS3 Protease Inhibitors from Philippine Medicinal Plants. Current Issues in Molecular Biology,
46(7), 7592–7618. https://doi.org/10.3390/cimb46070451
Deem, J. D., Faber, C. L., & Morton, G. J. (2021). AgRP neurons: Regulators of feeding, energy expenditure,
and behavior. The FEBS Journal, 289(8), 2362–2381. https://doi.org/10.1111/febs.16176
Fadil, W., Nuraini Harmastuti, Andri Prasetiyo, & Rina Herowati. (2023). Analysis of Molecular Docking and
Dynamics Simulation of Mahogany (Swietenia macrophylla King) Compounds Against the PLpro Enzyme
SARS-COV-2. Jurnal Farmasi Dan Ilmu Kefarmasian Indonesia/Jurnal Farmasi Dan Ilmu Kefarmasian
Indonesia, 10(3), 347–359. https://doi.org/10.20473/jfiki.v10i32023.347-359
Lafferty, R. A., Flatt, P . R., & Irwin, N. (2024). NPYR modulation: Potential for the next major advance in
obesity and type 2 diabetes management? Peptides, 179, 171256–171256.
https://doi.org/10.1016/j.peptides.2024.171256
Liu, Y ., Zhou, X., Zhou, D., Jian, Y ., Jia, J., & Ge, F. (2022). Isolation of Chalcomoracin as a Potential
α-Glycosidase Inhibitor from Mulberry Leaves and Its Binding Mechanism. Molecules, 27(18), 5742.
https://doi.org/10.3390/molecules27185742
Młynarska, E., Czarnik, W., Dzieża, N., Jędraszak, W., Majchrowicz, G., Prusinowski, F., Stabrawa, M., Rysz, J.,
& Franczyk, B. (2025). Type 2 Diabetes Mellitus: New Pathogenetic Mechanisms, Treatment and the
Most Important Complications. International Journal of Molecular Sciences, 26(3), 1094.
https://doi.org/10.3390/ijms26031094
Nestler, E. J., & Lüscher, C. (2019). The Molecular Basis of Drug Addiction: Linking Epigenetic to Synaptic and
Circuit Mechanisms. Neuron, 102(1), 48–59. https://doi.org/10.1016/j.neuron.2019.01.016
Ortiz Zacarías, N. V., Lenselink, E. B., IJzerman, A. P ., Handel, T. M., & Heitman, L. H. (2018). Intracellular
Receptor Modulation: Novel Approach to Target GPCRs. Trends in Pharmacological Sciences, 39(6),
547–559. https://doi.org/10.1016/j.tips.2018.03.002
Ramírez, D., & Caballero, J. (2018). Is It Reliable to Take the Molecular Docking Top Scoring Position as the
Best Solution without Considering Available Structural Data? Molecules, 23(5), 1038.
https://doi.org/10.3390/molecules23051038
Qiu, Tian, and Ou Fu. 2025.
“GPCRs in Hypothalamic Neurons and Their Roles in Controlling Food Intake
and Metabolism.
” Frontiers in Molecular Neuroscience 18, no. February (February).
https://doi.org/10.3389/fnmol.2025.1536577.
Rabal, P . M., & Coveñas, R. (2021). Regulation of homeostasis by neuropeptide Y: involvement in food
intake. Current Medicinal Chemistry, 28. https://doi.org/10.2174/0929867328666211213114711
Salahudeen, M. S., & Nishtala, P . S. (2017). An overview of pharmacodynamic modelling, ligand-binding
approach and its application in clinical practice. Saudi Pharmaceutical Journal, 25(2), 165–175.
https://doi.org/10.1016/j.jsps.2016.07.002
Shi, Y .
-C., Lau, J., Lin, Z., Zhang, H., Zhai, L., Sperk, G., Heilbronn, R., Mietzsch, M., Weger, S., Huang, X.
-F.,
Enriquez, R. F., Baldock, P . A., Zhang, L., Sainsbury, A., Herzog, H., & Lin, S. (2013). Arcuate NPY
controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the
PVN. Cell Metabolism, 17(2), 236–248. https://doi.org/10.1016/j.cmet.2013.01.006
17
First author et al.
Sigorski, Dawid, Aleksandra Sejda, Nouran Abualsaud, Ewa Krawczyk, Ewa Izycka-Swieszewska, and Joanna
Kitlinska. 2025.
“Neuropeptide Y in Cancer-Biological Functions and Potential Clinical Implications.
”
Cancer Metastasis Reviews 44, no. 1 (June): 21. https://doi.org/10.1007/s10555-024-10237-z.
Sousa, D., Lopes, E., Rosendo-Silva, D., & Matafome, P . (2023). The Bidirectional Relationship of NPY and
Mitochondria in Energy Balance Regulation. Biomedicines, 11(2), 446.
https://doi.org/10.3390/biomedicines11020446
World Health Organization. (2019). Mapping the health system response to childhood obesity in the WHO
European Region: an overview and country perspectives. Iris.who.int.
https://iris.who.int/handle/10665/346468
Wulansari, A., Martianto, D., & Baliwati, Y . F. (2016). ESTIMASI KERUGIAN EKONOMI AKIBAT OBESITAS PADA
ORANG DEWASA DI INDONESIA. Indonesian Journal of Nutrition and Food IPB, 11(2).
https://doi.org/10.25182/jgp.2016.11.2.%25p
Xiao, Y ., Lai, X., Wang, Z., Wang, S., Wu, Z., Liu, Q., Chen, M., & Zhou, S. (2024). Subarachnoid
haemorrhage‐induced reversible cardiac dysfunction: time course and potential mechanisms. ESC
Heart Failure, 11(3), 1625–1635. https://doi.org/10.1002/ehf2.14732
Xu, H., Liu, T., Dai, Y ., Li, N., & Cao, Z. (2025). The role of ERK1/2 signaling in diabetes: pathogenic and
therapeutic implications. Frontiers in Pharmacology, 16.
https://doi.org/10.3389/fphar.2025.1600251
Yang, Z., Han, S., Keller, M., Kaiser, A., Bender, B. J., Bosse, M., Burkert, K., Kögler, L. M., Wifling, D.,
Bernhardt, G., Plank, N., Littmann, T., Schmidt, P ., Yi, C., Li, B., Ye, S., Zhang, R., Xu, B., Larhammar,
D., & Stevens, R. C. (2018). Structural basis of ligand binding modes at the neuropeptide Y Y1
receptor. Nature, 556(7702), 520–524. https://doi.org/10.1038/s41586-018-0046-x.
Articles published in Indonesian Journal of Life Sciences are licensed under a Creative Commons Attribution-ShareAlike 4.0 International license. You are free to copy, transform, or redistribute articles for any lawful purpose in any medium, provided you give appropriate credit to the original author(s) and Indonesian Journal Life of Sciences, link to the license, indicate if changes were made, and redistribute any derivative work under the same license. Copyright on articles is retained by the respective author(s), without restrictions. A non-exclusive license is granted to Indonesian Journal Life of Sciences to publish the article and identify itself as its original publisher, along with the commercial right to include the article in a hardcopy issue for sale to libraries and individuals. By publishing in Indonesian Journal Life of Sciences, authors grant any third party the right to use their article to the extent provided by the Creative Commons Attribution-ShareAlike 4.0 International license.
