Computer-aided Discovery of Bioactive Natural Product Isoliquiritigenin as an Acetylcholinesterase Inhibitor
Keywords:
Acetylcholinesterase Inhibitor, Isoliquiritigenin, In Vitro Study, In Silico Study, Natural Products
Abstract
Bioactive natural products have been extensively investigated for the discovery of alternative Alzheimer’s disease (AD) treatments. Recently, our structure-based virtual screening (SBVS) campaigns on natural products served in the LOTUS database exhibited the potency of isoliquiritigenin as an acetylcholinesterase (AChE) inhibitor, which propelled us to investigate it further. This study aimed to evaluate the acetylcholinesterase (AChE) inhibitory activity of isoliquiritigenin compared to commonly known inhibitors i.e., donepezil through in vitro and in silico studies. The AChE inhibitory activity of isoliquiritigenin and donepezil was evaluated using the improved Ellman method and the molecular mechanism in inhibiting AChE was identified using molecular docking and dynamics simulations. Our findings verified the AChE inhibitory activity of isoliquiritigenin, possessing an IC50 value of 126.22 µM compared to donepezil with an IC50 value of 36.98 µM. In silico studies revealed that five best-docked poses from 100 redocking and molecular docking simulations established interactions in the AChE active site in 5 ns after 5-ns equilibration run. Further dynamics interactions were explored to 50 ns, showing interactions of isoliquiritigenin and donepezil which were still in the AChE active site. These simulations also revealed the pivotality of the aromatic ring and hydroxyl moiety of isoliquiritigenin reinforcing the receptor-ligand stabilization. Our studies hence exhibited the potency of isoliquiritigenin acting as an AChE inhibitor and might be explored in isoliquiritigenin-containing bioactive natural products as AD alternative treatments.
References
Ahmed, S., Khan, S. T., Zargaham, M. K., Khan, A. U., Khan, S., Hussain, A., Uddin, J., Khan, A., & Al-Harrasi, A. (2021). Potential therapeutic natural products against Alzheimer’s disease with Reference of Acetylcholinesterase. Biomedicine and Pharmacotherapy, 139, 111609. https://doi.org/10.1016/j.biopha.2021.111609
Chen, Y. C. (2015). Beware of docking! Trends in Pharmacological Sciences, 36(2), 78–95. https://doi.org/10.1016/J.TIPS.2014.12.001
Cho, J. K., Ryu, Y. B., Curtis-Long, M. J., Ryu, H. W., Yuk, H. J., Kim, D. W., Kim, H. J., Lee, W. S., & Park, K. H. (2012). Cholinestrase inhibitory effects of geranylated flavonoids from Paulownia tomentosa fruits. Bioorganic & Medicinal Chemistry, 20(8), 2595–2602. https://doi.org/10.1016/j.bmc.2012.02.044
Diallo, B. N., Swart, T., Hoppe, H. C., Tastan Bishop, Ö., & Lobb, K. (2021). Potential repurposing of four FDA approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay. Scientific Reports, 11(1), 1–15. https://doi.org/10.1038/s41598-020-80722-2
Dong, M., Yang, Z., Gao, Q., Deng, Q., Li, L., & Chen, H. (2024). Protective Effects of Isoliquiritigenin and Licochalcone B on the Immunotoxicity of BDE-47: Antioxidant Effects Based on the Activation of the Nrf2 Pathway and Inhibition of the NF-κB Pathway. Antioxidants, 13(4), 445. https://doi.org/10.3390/antiox13040445
Gajendra, K., Pratap, G. K., Poornima, D. V., Shantaram, M., & Ranjita, G. (2024). Natural acetylcholinesterase inhibitors: A multi-targeted therapeutic potential in Alzheimer’s disease. European Journal of Medicinal Chemistry Reports, 11(100154). https://doi.org/10.1016/j.ejmcr.2024.100154
Gaur, R., Yadav, K. S., Verma, R. K., Yadav, N. P., & Bhakuni, R. S. (2014). In vivo anti-diabetic activity of derivatives of isoliquiritigenin and liquiritigenin. Phytomedicine, 21(4), 415–422. https://doi.org/10.1016/j.phymed.2013.10.015
George, G., Koyiparambath, V. P., Sukumaran, S., Nair, A. S., Pappachan, L. K., Al-Sehemi, A. G., Kim, H., & Mathew, B. (2022). Structural Modifications on Chalcone Framework for Developing New Class of Cholinesterase Inhibitors. International Journal of Molecular Sciences, 23(3121). https://doi.org/10.3390/ijms23063121
Hafiz, Z. Z., Amin, M. ‘Afif M., James, R. M. J., Teh, L. K., Salleh, M. Z., & Adenan, M. I. (2020). Inhibitory Effects of Raw-Extract Centella asiatica (RECA) on Acetylcholinesterase, Inflammations, and Oxidative Stress Activities via In Vitro and In Vivo. Molecules, 25(4), 892.
Istyastono, E. P., Yuniarti, N., Prasasty, V. D., Mungkasi, S., Waskitha, S. S. W., Yanuar, M. R. S., & Riswanto, F. D. O. (2023). Caffeic acid in spent coffee grounds as a dual inhibitor for MMP-9 and DPP-4 enzymes. Molecules, 28(20), 1–12. https://doi.org/10.3390/molecules28207182
Ketenci, S., Acet, N. G., Sarıdoğan, G. E., Aydın, B., Cabadak, H., & Gören, M. Z. (2020). The Neurochemical Effects of Prazosin Treatment on Fear Circuitry in a Rat Traumatic Stress Model. Clinical Psychopharmacology and Neuroscience, 18(2), 219–230. https://doi.org/10.9758/cpn.2020.18.2.219
Khan, M. T. H., Orhan, I., Şenol, F. S., Kartal, M., Şener, B., Dvorská, M., Šmejkal, K., & Šlapetová, T. (2009). Cholinesterase inhibitory activities of some flavonoid derivatives and chosen xanthone and their molecular docking studies. Chemico-Biological Interactions, 181(3), 383–389. https://doi.org/10.1016/j.cbi.2009.06.024
Kim, J. Y., Lee, W. S., Kim, Y. S., Curtis-long, M. J., Lee, B. W., Ryu, Y. B., & Park, K. H. (2011). Isolation of Cholinesterase-Inhibiting Flavonoids from Morus lhou. Journal of Agricultural and Food Chemistry, 59(9), 4589–4596.
Konrath, E. L., Passos, C. D. S., Klein-Júnior, L. C., & Henriques, A. T. (2013). Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer’s disease. Journal of Pharmacy and Pharmacology, 65(12), 1701–1725. https://doi.org/10.1111/jphp.12090
Li, H., Ye, M., Zhang, Y., Huang, M., Xu, W., Chu, K., Chen, L., & Que, J. (2015). Blood-brain barrier permeability of Gualou Guizhi granules and neuroprotective effects in ischemia/reperfusion injury. Molecular Medicine Reports, 12(1), 1272–1278. https://doi.org/10.3892/mmr.2015.3520
Liu, K., & Kokubo, H. (2017). Exploring the stability of ligand binding modes to proteins by molecular dynamics simulations: a cross-docking study. Journal of Chemical Information and Modeling, 57(10), 2514–2522. https://doi.org/10.1021/ACS.JCIM.7B00412/SUPPL_FILE/CI7B00412_SI_001.PDF
Mahmood, N. D., Nasir, N. L. M., Rofiee, M. S., Tohid, S. F. M., Ching, S. M., Teh, L. K., Salleh, M. Z., & Zakaria, Z. A. (2014). Muntingia calabura: A review of its traditional uses, chemical properties, and pharmacological observations. Pharmaceutical Biology, 52(12), 1598–1623. https://doi.org/10.3109/13880209.2014.908397
Mohsin, N. U. A., & Ahmad, M. (2020). Donepezil: A review of the recent structural modifications and their impact on anti-alzheimer activity. Brazilian Journal of Pharmaceutical Sciences, 56(e18325), 1–16. https://doi.org/10.1590/S2175-97902019000418325
Nichols, E., Steinmetz, J. D., Vollset, S. E., Fukutaki, K., Chalek, J., Abd-Allah, F., Abdoli, A., Abualhasan, A., Abu-Gharbieh, E., Akram, T. T., Al Hamad, H., Alahdab, F., Alanezi, F. M., Alipour, V., Almustanyir, S., Amu, H., Ansari, I., Arabloo, J., Ashraf, T., … Vos, T. (2022). Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. The Lancet Public Health, 7(2), e105–e125. https://doi.org/10.1016/S2468-2667(21)00249-8
Riswanto, F. D. O., Hariono, M., Yuliani, S. H., & Istyastono, E. P. (2017). Computer-aided design of chalcone derivatives as lead compounds targeting acetylcholinesterase. Indonesian Journal of Pharmacy, 28(2), 100–111. https://doi.org/10.14499/indonesianjpharm28iss2pp100
Riswanto, F. D. O., Waskitha, S. S. W., Yanuar, M. R. S., & Enade. (2024). Structure-based virtual screening on a new open-source natural products database LOTUS to discover acetylcholinesterase ınhibitors. 28(4), 1099–1106.
Shi, D., Yang, J., Jiang, Y., Wen, L., Wang, Z., & Yang, B. (2020). The antioxidant activity and neuroprotective mechanism of isoliquiritigenin. Free Radical Biology and Medicine, 152, 207–215. https://doi.org/10.1016/j.freeradbiomed.2020.03.016
Sugimoto, H. (1999). Structure-activity relationships of acetylcholinesterase inhibitors: Donepezil hydrochloride for the treatment of Alzheimer’s Disease. Pure and Applied Chemistry, 71(11), 2031–2037.
Wang, K. L., Yu, Y. C., & Hsia, S. M. (2021). Perspectives on the role of isoliquiritigenin in cancer. Cancers, 13(15), 1–37. https://doi.org/10.3390/CANCERS13010115
Waskitha, S. S. W., Istyastono, E. P., & Riswanto, F. D. O. (2023). Molecular docking study of caffeic acid as acetylcholinesterase inhibitor. Journal of Food and Pharmaceutical Sciences, 11(3), 867–873. https://doi.org/10.22146/jfps.7665
Windah, A. L. L., & Istyastono, E. P. (2024). Computational studies of donepezil and acetylcholinesterase molecular dynamics interactions. Jurnal Farmasi Sains Dan Komunitas, 21(1), 91–99.
Zhang, X., Yeung, E. D., Wang, J., Panzhinskiy, E. E., Tong, C., Li, W., & Li, J. (2010). Isoliquiritigenin, a natural anti-oxidant, selectively inhibits the proliferation of prostate cancer cells. Clinical and Experimental Pharmacology and Physiology, 37(8), 841–847. https://doi.org/10.1111/j.1440-1681.2010.05395.x
Chen, Y. C. (2015). Beware of docking! Trends in Pharmacological Sciences, 36(2), 78–95. https://doi.org/10.1016/J.TIPS.2014.12.001
Cho, J. K., Ryu, Y. B., Curtis-Long, M. J., Ryu, H. W., Yuk, H. J., Kim, D. W., Kim, H. J., Lee, W. S., & Park, K. H. (2012). Cholinestrase inhibitory effects of geranylated flavonoids from Paulownia tomentosa fruits. Bioorganic & Medicinal Chemistry, 20(8), 2595–2602. https://doi.org/10.1016/j.bmc.2012.02.044
Diallo, B. N., Swart, T., Hoppe, H. C., Tastan Bishop, Ö., & Lobb, K. (2021). Potential repurposing of four FDA approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay. Scientific Reports, 11(1), 1–15. https://doi.org/10.1038/s41598-020-80722-2
Dong, M., Yang, Z., Gao, Q., Deng, Q., Li, L., & Chen, H. (2024). Protective Effects of Isoliquiritigenin and Licochalcone B on the Immunotoxicity of BDE-47: Antioxidant Effects Based on the Activation of the Nrf2 Pathway and Inhibition of the NF-κB Pathway. Antioxidants, 13(4), 445. https://doi.org/10.3390/antiox13040445
Gajendra, K., Pratap, G. K., Poornima, D. V., Shantaram, M., & Ranjita, G. (2024). Natural acetylcholinesterase inhibitors: A multi-targeted therapeutic potential in Alzheimer’s disease. European Journal of Medicinal Chemistry Reports, 11(100154). https://doi.org/10.1016/j.ejmcr.2024.100154
Gaur, R., Yadav, K. S., Verma, R. K., Yadav, N. P., & Bhakuni, R. S. (2014). In vivo anti-diabetic activity of derivatives of isoliquiritigenin and liquiritigenin. Phytomedicine, 21(4), 415–422. https://doi.org/10.1016/j.phymed.2013.10.015
George, G., Koyiparambath, V. P., Sukumaran, S., Nair, A. S., Pappachan, L. K., Al-Sehemi, A. G., Kim, H., & Mathew, B. (2022). Structural Modifications on Chalcone Framework for Developing New Class of Cholinesterase Inhibitors. International Journal of Molecular Sciences, 23(3121). https://doi.org/10.3390/ijms23063121
Hafiz, Z. Z., Amin, M. ‘Afif M., James, R. M. J., Teh, L. K., Salleh, M. Z., & Adenan, M. I. (2020). Inhibitory Effects of Raw-Extract Centella asiatica (RECA) on Acetylcholinesterase, Inflammations, and Oxidative Stress Activities via In Vitro and In Vivo. Molecules, 25(4), 892.
Istyastono, E. P., Yuniarti, N., Prasasty, V. D., Mungkasi, S., Waskitha, S. S. W., Yanuar, M. R. S., & Riswanto, F. D. O. (2023). Caffeic acid in spent coffee grounds as a dual inhibitor for MMP-9 and DPP-4 enzymes. Molecules, 28(20), 1–12. https://doi.org/10.3390/molecules28207182
Ketenci, S., Acet, N. G., Sarıdoğan, G. E., Aydın, B., Cabadak, H., & Gören, M. Z. (2020). The Neurochemical Effects of Prazosin Treatment on Fear Circuitry in a Rat Traumatic Stress Model. Clinical Psychopharmacology and Neuroscience, 18(2), 219–230. https://doi.org/10.9758/cpn.2020.18.2.219
Khan, M. T. H., Orhan, I., Şenol, F. S., Kartal, M., Şener, B., Dvorská, M., Šmejkal, K., & Šlapetová, T. (2009). Cholinesterase inhibitory activities of some flavonoid derivatives and chosen xanthone and their molecular docking studies. Chemico-Biological Interactions, 181(3), 383–389. https://doi.org/10.1016/j.cbi.2009.06.024
Kim, J. Y., Lee, W. S., Kim, Y. S., Curtis-long, M. J., Lee, B. W., Ryu, Y. B., & Park, K. H. (2011). Isolation of Cholinesterase-Inhibiting Flavonoids from Morus lhou. Journal of Agricultural and Food Chemistry, 59(9), 4589–4596.
Konrath, E. L., Passos, C. D. S., Klein-Júnior, L. C., & Henriques, A. T. (2013). Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer’s disease. Journal of Pharmacy and Pharmacology, 65(12), 1701–1725. https://doi.org/10.1111/jphp.12090
Li, H., Ye, M., Zhang, Y., Huang, M., Xu, W., Chu, K., Chen, L., & Que, J. (2015). Blood-brain barrier permeability of Gualou Guizhi granules and neuroprotective effects in ischemia/reperfusion injury. Molecular Medicine Reports, 12(1), 1272–1278. https://doi.org/10.3892/mmr.2015.3520
Liu, K., & Kokubo, H. (2017). Exploring the stability of ligand binding modes to proteins by molecular dynamics simulations: a cross-docking study. Journal of Chemical Information and Modeling, 57(10), 2514–2522. https://doi.org/10.1021/ACS.JCIM.7B00412/SUPPL_FILE/CI7B00412_SI_001.PDF
Mahmood, N. D., Nasir, N. L. M., Rofiee, M. S., Tohid, S. F. M., Ching, S. M., Teh, L. K., Salleh, M. Z., & Zakaria, Z. A. (2014). Muntingia calabura: A review of its traditional uses, chemical properties, and pharmacological observations. Pharmaceutical Biology, 52(12), 1598–1623. https://doi.org/10.3109/13880209.2014.908397
Mohsin, N. U. A., & Ahmad, M. (2020). Donepezil: A review of the recent structural modifications and their impact on anti-alzheimer activity. Brazilian Journal of Pharmaceutical Sciences, 56(e18325), 1–16. https://doi.org/10.1590/S2175-97902019000418325
Nichols, E., Steinmetz, J. D., Vollset, S. E., Fukutaki, K., Chalek, J., Abd-Allah, F., Abdoli, A., Abualhasan, A., Abu-Gharbieh, E., Akram, T. T., Al Hamad, H., Alahdab, F., Alanezi, F. M., Alipour, V., Almustanyir, S., Amu, H., Ansari, I., Arabloo, J., Ashraf, T., … Vos, T. (2022). Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. The Lancet Public Health, 7(2), e105–e125. https://doi.org/10.1016/S2468-2667(21)00249-8
Riswanto, F. D. O., Hariono, M., Yuliani, S. H., & Istyastono, E. P. (2017). Computer-aided design of chalcone derivatives as lead compounds targeting acetylcholinesterase. Indonesian Journal of Pharmacy, 28(2), 100–111. https://doi.org/10.14499/indonesianjpharm28iss2pp100
Riswanto, F. D. O., Waskitha, S. S. W., Yanuar, M. R. S., & Enade. (2024). Structure-based virtual screening on a new open-source natural products database LOTUS to discover acetylcholinesterase ınhibitors. 28(4), 1099–1106.
Shi, D., Yang, J., Jiang, Y., Wen, L., Wang, Z., & Yang, B. (2020). The antioxidant activity and neuroprotective mechanism of isoliquiritigenin. Free Radical Biology and Medicine, 152, 207–215. https://doi.org/10.1016/j.freeradbiomed.2020.03.016
Sugimoto, H. (1999). Structure-activity relationships of acetylcholinesterase inhibitors: Donepezil hydrochloride for the treatment of Alzheimer’s Disease. Pure and Applied Chemistry, 71(11), 2031–2037.
Wang, K. L., Yu, Y. C., & Hsia, S. M. (2021). Perspectives on the role of isoliquiritigenin in cancer. Cancers, 13(15), 1–37. https://doi.org/10.3390/CANCERS13010115
Waskitha, S. S. W., Istyastono, E. P., & Riswanto, F. D. O. (2023). Molecular docking study of caffeic acid as acetylcholinesterase inhibitor. Journal of Food and Pharmaceutical Sciences, 11(3), 867–873. https://doi.org/10.22146/jfps.7665
Windah, A. L. L., & Istyastono, E. P. (2024). Computational studies of donepezil and acetylcholinesterase molecular dynamics interactions. Jurnal Farmasi Sains Dan Komunitas, 21(1), 91–99.
Zhang, X., Yeung, E. D., Wang, J., Panzhinskiy, E. E., Tong, C., Li, W., & Li, J. (2010). Isoliquiritigenin, a natural anti-oxidant, selectively inhibits the proliferation of prostate cancer cells. Clinical and Experimental Pharmacology and Physiology, 37(8), 841–847. https://doi.org/10.1111/j.1440-1681.2010.05395.x
Published
2025-03-27
How to Cite
Waskitha, S. S. W., Istyastono, E. P., Gani, M. R., & Riswanto, F. D. O. (2025). Computer-aided Discovery of Bioactive Natural Product Isoliquiritigenin as an Acetylcholinesterase Inhibitor. Indonesian Journal of Pharmacy. https://doi.org/10.22146/ijp.16538
Issue
Section
Research Article
