STRUCTURE-BASED INVESTIGATION OF CURCUMIN–hIAPP FIBRIL INTERACTIONS THROUGH MOLECULAR DOCKING AND ADMET PROFILING
Keywords:
Curcumin, hIAPP fibril, Molecular docking, Amyloid aggregation, ADMET
Abstract
Human islet amyloid polypeptide (hIAPP) aggregation and fibril formation is linked to pancreatic β-cell dysfunction in type 2 diabetes mellitus, and hIAPP could be a target molecule for anti-amyloid strategies. The molecular docking, binding interaction analysis and in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) profiling of the interaction of curcumin with the hIAPP fibril were investigated in this study. The top nine docking poses predicted by AutoDock Vina have binding affinities ranging from −6.0 to −5.8 kcal/mol, and the most favorable docking pose has a binding affinity of −6.0 kcal/mol. The results from the interaction analysis showed that there is a multiresidue binding network around Ser20, Asn21, Asn22, Leu27, and Ser28 with conventional hydrogen bond, van der Waals contact and hydrophobic interaction. Curcumin showed moderate lipophilicity and suitable molecular size, but also low aqueous solubility, high plasma protein binding (PPB), low predicted BBB penetration, and high predicted BSEP, CYP1A2 and CYP2B6 inhibition. Comparatively low likelihoods for several endpoints were observed in toxicity predictions, whereas skin sensitization, respiratory toxicity, and hERG-related liability appeared as notable computational alerts. Overall, curcumin had a plausible predicted binding configuration with the hIAPP fibril and pharmacokinetic and safety limitations. These findings are the basis for further molecular dynamics, experimental fibrillation, pharmacokinetic and toxicity studies.
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References
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4.Bishoyi, A. K., Roham, P. H., Rachineni, K., Save, S., Hazari, M. A., Sharma, S., & Kumar, A. (2021). Human islet amyloid polypeptide (hIAPP)-a curse in type II diabetes mellitus: insights from structure and toxicity studies. Biological chemistry, 402(2), 133-153.
5.Bortoletto, A. S., Graham, W. V., Trout, G., Bonito‐Oliva, A., Kazmi, M. A., Gong, J., ... & Parchem, R. J. (2022). Human islet amyloid polypeptide (hIAPP) protofibril‐specific antibodies for detection and treatment of type 2 diabetes. Advanced Science, 9(34), 2202342.
6.Bousch, C., Bérubé, F., Babych, M., Ongeri, S., & Bourgault, S. (2026). Molecular mechanisms of islet amyloid polypeptide aggregation: towards chemical strategies to prevent amyloid formation and to design non-aggregating peptide therapeutics. International Journal of Molecular Sciences, 27(6), 2598.
7.Bučević Popović, V., Karahmet Farhat, E., Banjari, I., Jeličić Kadić, A., & Puljak, L. (2024). Bioavailability of oral curcumin in systematic reviews: a methodological study. Pharmaceuticals, 17(2), 164.
8.Cao, Q., Boyer, D. R., Sawaya, M. R., Abskharon, R., Saelices, L., Nguyen, B. A., ... & Eisenberg, D. S. (2021). Cryo-EM structures of hIAPP fibrils seeded by patient-extracted fibrils reveal new polymorphs and conserved fibril cores. Nature structural & molecular biology, 28(9), 724-730.
9.Cao, Q., Boyer, D. R., Sawaya, M. R., Ge, P., & Eisenberg, D. S. (2020). Cryo-EM structure and inhibitor design of human IAPP (amylin) fibrils. Nature structural & molecular biology, 27(7), 653-659.
10.Doytchinova, I., Atanasova, M., Salamanova, E., Ivanov, S., & Dimitrov, I. (2020). Curcumin inhibits the primary nucleation of amyloid-beta peptide: A molecular dynamics study. Biomolecules, 10(9), 1323.
11.Eberhardt, J., Santos-Martins, D., Tillack, A. F., & Forli, S. (2021). AutoDock Vina 1.2. 0: new docking methods, expanded force field, and python bindings. Journal of chemical information and modeling, 61(8), 3891.
12.Fu, L., Shi, S., Yi, J., Wang, N., He, Y., Wu, Z., ... & Cao, D. (2024). ADMETlab 3.0: an updated comprehensive online ADMET prediction platform enhanced with broader coverage, improved performance, API functionality and decision support. Nucleic acids research, 52(W1), W422-W431.
13.Gallardo, R., Iadanza, M. G., Xu, Y., Heath, G. R., Foster, R., Radford, S. E., & Ranson, N. A. (2020). Fibril structures of diabetes-related amylin variants reveal a basis for surface-templated assembly. Nature structural & molecular biology, 27(11), 1048-1056.
14.Garcia-Vinuales, S., Ilie, I. M., Santoro, A. M., Romanucci, V., Zarrelli, A., Di Fabio, G., ... & Milardi, D. (2022). Silybins inhibit human IAPP amyloid growth and toxicity through stereospecific interactions. Biochimica et Biophysica Acta (BBA)-Proteins and Proteomics, 1870(5), 140772.
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16.Jakubowski, J. M., Orr, A. A., Le, D. A., & Tamamis, P. (2020). Interactions between Curcumin Derivatives and Amyloid β Fibrils: Insights from Molecular Dynamics Simulations. Journal of Chemical Information and Modeling, 60(1), 289-305.
17.Jamrozik, E., Smieja, M., & Podlewska, S. (2024). ADMET-PrInt: evaluation of ADMET properties: prediction and interpretation. Journal of Chemical Information and Modeling, 64(5), 1425-1432.
18.Kaur, A., & Goyal, B. (2024). In silico design and identification of new peptides for mitigating hIAPP aggregation in type 2 diabetes. Journal of Biomolecular Structure and Dynamics, 42(19), 10006-10021.
19.Khurshid, B., Rehman, A. U., Muhammad, S., Wadood, A., & Anwar, J. (2022). Toward the Noninvasive Diagnosis of Alzheimer’s Disease: Molecular Basis for the Specificity of Curcumin for Fibrillar Amyloid β. ACS omega, 7(25), 22032-22038.
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21.Mahboob, A., Senevirathne, D. K. L., Paul, P., Nabi, F., Khan, R. H., & Chaari, A. (2023). An investigation into the potential action of polyphenols against human Islet Amyloid Polypeptide aggregation in type 2 diabetes. International journal of biological macromolecules, 225, 318-350.
22.Nguyen, P. H., Ramamoorthy, A., Sahoo, B. R., Zheng, J., Faller, P., Straub, J. E., ... & Derreumaux, P. (2021). Amyloid oligomers: A joint experimental/computational perspective on Alzheimer’s disease, Parkinson’s disease, type II diabetes, and amyotrophic lateral sclerosis. Chemical reviews, 121(4), 2545.
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24.Rani, D., Priyadarshi, N., Goyal, D., Singhal, N. K., & Goyal, B. (2026). Synergistic Effect of Mutations in the Amyloidogenic Core of Human Amylin (hAM) Affords a New Potent Inhibitor of hAM Fibrillation: Computational Design and Experimental Validation. ACS Chemical Neuroscience, 17(3), 504-524.
25.Rani, D., Priyadarshi, N., Singhal, N. K., & Goyal, B. (2025). Modulation of hIAPP Fibrillation by Rationally Designed Hexapeptides Revealed by Molecular Dynamics and Experimental Investigations. ACS Chemical Neuroscience, 16(13), 2485-2501.
26.Roham, P. H., Save, S. N., & Sharma, S. (2022). Human islet amyloid polypeptide: A therapeutic target for the management of type 2 diabetes mellitus. Journal of Pharmaceutical Analysis, 12(4), 556-569.
27.Saini, R. K., Goyal, D., & Goyal, B. (2020). Targeting human islet amyloid polypeptide aggregation and toxicity in type 2 diabetes: An overview of peptide-based inhibitors. Chemical Research in Toxicology, 33(11), 2719-2738.
28.Suladze, S., Sustay Martinez, C., Rodriguez Camargo, D. C., Engler, J., Rodina, N., Sarkar, R., ... & Reif, B. (2024). Structural insights into seeding mechanisms of hIAPP fibril formation. Journal of the American Chemical Society, 146(20), 13783-13796.
29.Tabanelli, R., Brogi, S., & Calderone, V. (2021). Improving curcumin bioavailability: current strategies and future perspectives. Pharmaceutics, 13(10), 1715.
30.Tang, Y., Zhang, D., Zhang, Y., Liu, Y., Gong, X., Chang, Y., ... & Zheng, J. (2020). Introduction and fundamentals of human islet amyloid polypeptide inhibitors. ACS Applied Bio Materials, 3(12), 8286-8308.
31.Thota, R. N., Rosato, J. I., Dias, C. B., Burrows, T. L., Martins, R. N., & Garg, M. L. (2020). Dietary supplementation with curcumin reduces circulating levels of glycogen synthase kinase-3β and islet amyloid polypeptide in adults with high risk of type 2 diabetes and Alzheimer’s disease. Nutrients, 12(4), 1032.
32.Utomo, R. Y., Asawa, Y., Okada, S., Ban, H. S., Yoshimori, A., Bajorath, J., & Nakamura, H. (2021). Development of curcumin-based amyloid β aggregation inhibitors for Alzheimer's disease using the SAR matrix approach. Bioorganic & Medicinal Chemistry, 46, 116357.
Published
2026-05-26
How to Cite
Arjun K. Sharma, & Priya N. Verma. (2026). STRUCTURE-BASED INVESTIGATION OF CURCUMIN–hIAPP FIBRIL INTERACTIONS THROUGH MOLECULAR DOCKING AND ADMET PROFILING . IJRDO - JOURNAL OF BIOLOGICAL SCIENCE, 12(2), 88-105. https://doi.org/10.69980/bs.v12i2.6805
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