Pharmacokinetic Virtual Screening and Molecular Docking Simulation for Evaluating Cytochrome P450 CYP3A4 Interactions Between Glibenclamide and Eurycoma longifolia Jack Extract

Puti Isnaini; Prajona Marbun; Purwantiningsih Purwantiningsih; Agung Endro Nugroho

doi:10.22146/farmaseutik.v21i1.102022

Pharmacokinetic Virtual Screening and Molecular Docking Simulation for Evaluating Cytochrome P450 CYP3A4 Interactions Between Glibenclamide and Eurycoma longifolia Jack Extract

https://doi.org/10.22146/farmaseutik.v21i1.102022

Puti Isnaini⁽¹⁾, Prajona Marbun⁽²⁾, Purwantiningsih Purwantiningsih^(3*), Agung Endro Nugroho⁽⁴⁾

(1) Master Program of Pharmaceutical Science and Technology, Faculty of Pharmacy, Universitas Gadjah Mada
(2) Undergraduate Student in Pharmaceutical Science, Faculty of Pharmacy, Universitas Gadjah Mada
(3) Department Pharmacology and Clinically Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada
(4) Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada
(*) Corresponding Author

Abstract

Type 2 diabetes mellitus is a chronic disease with a globally increasing prevalence. The treatment of diabetes mellitus involves oral blood glucose-lowering agents, including glibenclamide. Although effective, glibenclamide can cause severe hypoglycemia, leading people to often combine it with herbal remedies such as the root extract of Eurycoma longifolia (ELRE), commonly known in Malaysia and Indonesia as the herbal medicine Tongkat Ali. ELRE is known for its anti-diabetic effects through enhanced insulin sensitivity and antioxidant activity. However, the pharmacokinetic interaction between ELRE and glibenclamide, particularly involving CYP3A4, which metabolizes glibenclamide, has not been well studied. This study employed an in silico approach using pharmacokinetic virtual screening server, followed by molecular docking analysis to evaluate the potential interaction. The results indicated that nearly all of the investigated ELRE chemical constituents showed high predicted affinity, with two compounds, 14,15β-dihydroxyklaineanone and niloticin, exhibiting higher affinity than glibenclamide for CYP3A4. These compounds may act as competitive substrates, potentially influencing glibenclamide metabolism.

Keywords

Eurycoma longifolia; Glibenclamide; CYP3A4; In Silico

Full Text:

PDF

References

Khan, M. A. B., Hashim, M. J., Kwan King, J., Govender, R. D., Mustafa, H., & Al Kaabi, J. (2020). Epidemiology of type 2 diabetes – Global burden of disease and forecasted trends. Journal of Epidemiology and Global Health, 10(1), 107–111. https://doi.org/10.2991/jegh.k.191028.001

Costello, R. A., Nicolas, S., & Shivkumar, A. (2023, July 12). Sulfonylureas. In StatPearls. MCPHS University; St. Bernards Hospital, Jonesboro-AR. https://www.ncbi.nlm.nih.gov/books/NBK513225/

Majidi Wizneh, F., & Asmawi, M. Z. (2014). Eurycoma longifolia Jack (Simarubaceae); Advances in its medicinal potentials. Pharmacognosy Journal, 6(4), July–August. https://www.phcogj.com/article/1520

Rehman, S. U., Choe, K., & Yoo, H. H. (2016). Review on a traditional herbal medicine, Eurycoma longifolia Jack (Tongkat Ali): Its traditional uses, chemistry, evidence-based pharmacology and toxicology. Molecules, 21(3), 331. https://doi.org/10.3390/molecules21030331

Abubakar, B. M., Salleh, F. M., & Wagiran, A. (2017). Chemical composition of Eurycoma longifolia (Tongkat Ali) and the quality control of its herbal medicinal products. Journal of Applied Sciences, 17(7), 324–338. https://doi.org/10.3923/jas.2017.324.338

Marbun, P., Hakim, A. R., Ujiantari, N. S. O., Sudarmanto, B. S. A., & Nugroho, A. E. (2023). In silico pharmacokinetics study of 2,5-dibenzylidenecyclopentanone analogs as mono-ketone versions of curcumin. BIO Web of Conferences, 75, 04002. https://doi.org/10.1051/bioconf/20237504002

Marbun, P., Nugroho, A. E., & Sudarmanto, B. S. A. (2023). Prediction of pharmacokinetic properties and in silico study of 2,5-dibenzylidenecyclopentanone analogs as oxidoreductase inhibitor in phase I metabolism targeting CYP3A4 (Undergraduate thesis). Faculty of Pharmacy, Universitas Gadjah Mada. Retrieved from https://etd.repository.ugm.ac.id/penelitian/detail/230870

Asha, R. N., Nayagam, B. R. D., & Bhuvanesh, N. (2021). Synthesis, molecular docking, and in silico ADMET studies of 4-benzyl-1-(2,4,6-trimethyl-benzyl)-piperidine: Potential inhibitor of SARS-CoV2. Bioorganic Chemistry, 112, 104967. https://doi.org/10.1016/j.bioorg.2021.104967

Fu, L., Shi, S., Yi, J., Wang, N., He, Y., Wu, Z., Peng, J., Deng, Y., Wang, W., Wu, C., Lyu, A., Zeng, X., Zhao, W., Hou, T., & 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. https://doi.org/10.1093/nar/gkae236

Agu, P. C., Afiukwa, C. A., Orji, O. U., Ezeh, E. M., Ofoke, I. H., Ogbu, C. O., Ugwuja, E. I., & Aja, P. M. (2023). Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in diseases management. Scientific Reports, 13, 13398. https://doi.org/10.1038/s41598-023-40160-2

Torres PHM, Sodero ACR, Jofily P, Silva-Jr FP. Key Topics in Molecular Docking for Drug Design. Int J Mol Sci. 2019 Sep 15;20(18):4574. doi: 10.3390/ijms20184574 . PMID: 31540192; PMCID: PMC6769580.

Naritomi, Y., Terashita, S., & Kagayama, A. (2004). Identification and relative contributions of human cytochrome P450 isoforms involved in the metabolism of glibenclamide and lansoprazole: Evaluation of an approach based on the in vitro substrate disappearance rate. Xenobiotica, 34(5), 415–427. https://doi.org/10.1080/00498250410001685728

Zharikova, O. L., Fokina, V. M., Nanovskaya, T. N., Hill, R. A., Mattison, D. R., Hankins, G. D. V., & Ahmed, M. S. (2009). Identification of the major human hepatic and placental enzymes responsible for the biotransformation of glyburide. Biochemical Pharmacology, 78(12), 1483–1490. https://doi.org/10.1016/j.bcp.2009.08.003

Mena-Ulecia K, Tiznado W, Caballero J (2015) Study of the Differential Activity of Thrombin Inhibitors Using Docking, QSAR, Molecular Dynamics, and MM-GBSA. PLoS ONE 10(11): e0142774. https://doi.org/10.1371/journal.pone.0142774

Zhou, L., Naraharisetti, S. B., Liu, L., Wang, H., Lin, Y. S., Isoherranen, N., Unadkat, J. D., Hebert, M. F., & Mao, Q. (2010). Contributions of human cytochrome P450 enzymes to glyburide metabolism. Biopharmaceutics & Drug Disposition, 31(4), 228–242. https://doi.org/10.1002/bdd.706

Molecular Operating Environment (MOE), 2024.06 Chemical Computing Group ULC, 910-1010 Sherbrooke St. W., Montreal, QC H3A 2R7, 2024.

Lipinski, C. A. (2004). Lead- and drug-like compounds: the rule-of-five revolution. Drug Discovery Today: Technologies, 1(4), 337-341. https://doi.org/10.1016/j.ddtec.2004.11.007

Sevrioukova, I. F., & Poulos, T. L. (2012). Structural and mechanistic insights into the interaction of cytochrome P450 3A4 with bromoergocryptine, a type I ligand. Journal of Biological Chemistry, 287(5), 3510-3517. https://doi.org/10.1074/jbc.M111.317081 Atomic coordinates and structure factors (code 3UA1) have been deposited in the Protein Data Bank (https://www.rcsb.org/structure/3ua1 ). Published under a Creative Commons Attribution (CC BY 4.0) license.

Purwantiningsih, A., Ismail, S., Hussin, A. H. J., & Chan, K. L. (2014). Inhibitory effect of Eurycoma longifolia extract and eurycomanone on human cytochrome P450 isoforms. International Journal of Pharmacy and Pharmaceutical Sciences, 6(6), 441–444.

Yan, Y., Wu, J., Hu, G., Gao, C., Guo, L., Chen, X., Liu, L., & Song, W. (2022). Current state and future perspectives of cytochrome P450 enzymes for C–H and C=C oxygenation. Synthetic and Systems Biotechnology, 7(3), 887–899. https://doi.org/10.1016/j.synbio.2022.05.005

Sevrioukova, I. F., & Poulos, T. L. (2012). Structural and mechanistic insights into the interaction of cytochrome P4503A4 with bromoergocryptine, a type I ligand. Enzymology, 287(5), 3510–3517. https://doi.org/10.1074/jbc.M111.317081

Hollingsworth, S. A., & Dror, R. O. (2018). Molecular dynamics simulation for all. Neuron, 99(6), 1129–1143. https://doi.org/10.1016/j.neuron.2018.08.011

DOI: https://doi.org/10.22146/farmaseutik.v21i1.102022