Malaysian Journal of Analytical Sciences, Vol 28 No 3 (2024): 530 - 542

INVESTIGATIONS ON THE INCLUSION OF BETULINIC ACID INTO CD-MOF-1 PERFORMED BY QUANTUM MECHANICS CALCULATIONS AND MOLECULAR DOCKING SIMULATION

(Kajian Kemasukan Asid Betulinik ke dalam CD-MOF-1 Melalui Pengiraan Mekanik Kuantum dan Simulasi Dok Molekul)

Saurelle Kenfack Tiofack^1,2, Mostafa Yousefzadeh Borzehandani¹, Patrice Kenfack Tsobnang²,

Muhammad Alif Mohamad Latif^1,3, Bimo Ario Tejo^1,3, Haslina Ahmad^1,3, Jean Ngoune²,

and Mohd Basyaruddin Abdul Rahman^1,3*

¹Integrated Chemical BioPhysics Research, Faculty of Science, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia.

²Department of Chemistry, University of Dschang, P. O. Box 67, Dschang, Cameroon

³Foundry of Reticular Materials for Sustainability, Institute of Nanoscience and Nanotechnology, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia

^*Corresponding author: basya@upm.edu.my

Received: 5 February 2024; Accepted: 16 April 2024; Published: 29 June 2024

Abstract

In recent years, CycloDextrin Metal-Organic Frameworks (CD-MOFs) have been investigated to develop potential drug carriers and improve the solubility of some molecules by their encapsulation. Betulinic acid (BA) or 3β-hydroxy-lup-20(29)-en-28-oic acid is a pentacyclic triterpene of the lupane family which has a wide range of biological activities, and it is considered a promising candidate for clinical application but, its high hydrophobicity and limited aqueous solubility contribute to its poor bioavailability. In this work, we show through computational studies that CD-MOF-1 can strongly encapsulate betulinic acid molecules through hydrogen bond interactions. For this purpose, the optimized geometry of BA was implemented by the Density Functional Theory using the function of Becke, Lee, Yang, and Parr (DFT/B3LYP) method with a 6-31+G(d) basis set using the Gaussian09 program and GaussView 5.0 for visualization. We noticed that BA has a lower energy gap (Egap = 6.1615 eV) indicating that it is soft, less stable, more reactive, and polarizable. According to the map of electrostatic potential (MEP), the active site of betulinic acid is the carboxylic group and the latter molecule preferred electrophilic attacks. The molecular docking was performed using AutoDock Vina v1.1.2 program and Discovery Studio Visualizer 16.1. The best binding affinities of BA and CD-MOF-1 had the lowest values of -8.2 KCal/mol and -11.5 KCal/mol for the simple and the packed CDMOF-1 structure respectively. The docking revealed that BA bound in the hydrophobic cavities of CD-MOF-1 through hydrogen bonds interactions which are [CD-MOF-1_OH13···_O28BA (2.95 Å)], [CD-MOF-1_O13···_H30BA (2.54 Å)], and [CD-MOF-1_OH12···_H30BA (2.12 Å)] for the simplest structure and [CD-MOF-1_OH12A···_O28BA (3.00 Å)], [CD-MOF-1_H13A···_H30BA (2.72 Å)] and [CD-MOF-1_OH2A···_H30BA (2.66 Å)] for the packed structure 1×1×1. The packed CD-MOF-1 structure is the best with accurate results, this may be the factor of enhancement of betulinic acid solubility and bioavailability. The present theoretical results indicate the possibility of forming the host-guest inclusion complex between BA and CD-MOF-1 which may enhance the solubility of BA and then its efficiency for drug delivery.

Keywords: CD-MOF, betulinic acid, quantum mechanics, molecular docking, solubility

Abstrak

Kebelakangan ini, pembangunan kerangka kerja logam-organik siklodekstrin (CD-MOF) telah dikaji sebagai pembawa ubat yang berpotensi dan meningkatkan keterlarutan beberapa molekul melalui pengkapsulan mereka. Asid betulinik (BA) atau asid 3β-hidroksi-lup-20(29)-en-28-oik ialah triterpena pentasiklik daripada keluarga lupana yang mempunyai pelbagai aktiviti biologi, dan ia dianggap sebagai calon yang berpotensi untuk aplikasi klinikal, namun hidrofobisitinya yang tinggi dan keterlarutan dalam air yang terhad menyumbang kepada bioavailabilitinya yang lemah. Dalam kajian ini, kajian pengiraan menunjukkan bahawa CD-MOF-1 boleh memerangkap molekul asid betulinik dengan kuat melalui interaksi ikatan hidrogen. Untuk tujuan ini, geometri BA yang optimum telah dilaksanakan melalui kaedah Teori fungsi ketumpatan menggunakan fungsi Becke, Lee, Yang, dan Parr (DFT/B3LYP) dengan set asas 6-31+G(d) menggunakan program Gaussian09 dan GaussView 5.0 untuk visualisasi. Kami mendapati bahawa BA mempunyai jurang tenaga yang lebih rendah (Egap = 6.1615 eV) menunjukkan bahawa ia lembut, kurang stabil, lebih reaktif dan boleh dipolarisasi. Menurut peta potensi elektrostatik (MEP), tapak aktif asid betulinik ialah kumpulan karboksilik dan molekul terakhir lebih cenderung kepada serangan elektrofilik. Pendokkan molekul telah dilakukan menggunakan program AutoDock Vina v1.1.2 dan Discovery Studio Visualizer 16.1. Perkaitan pengikatan terbaik BA dan CD-MOF-1 mempunyai nilai terendah -8.2 KCal/mol dan -11.5 KCal/mol untuk struktur CDMOF-1 yang ringkas dan padat. Pendokkan mendedahkan bahawa BA terikat dalam rongga hidrofobik CD-MOF-1 melalui interaksi ikatan hidrogen iaitu [CD-MOF-1_OH13···_O28BA (2.95 Å)], [CD-MOF-1_O13···_H30BA (2.54 Å)], and [CD-MOF-1_OH12···_H30BA (2.12 Å)] untuk struktur paling ringkas dan [CD-MOF-1_OH12A···_O28BA (3.00 Å)], [CD-MOF-1_H13A···_H30BA (2.72 Å)] and [CD-MOF-1_OH2A···_H30BA (2.66 Å)] untuk struktur tersusun 1×1×1. Struktur CD-MOF-1 tersusun adalah yang terbaik dengan hasil yang tepat, yang berkemungkinan faktor peningkatan keterlarutan asid betulinik dan bioavailabiliti. Keputusan teori semasa menunjukkan kemungkinan pembentukan kompleks kemasukan hos antara BA dan CD-MOF-1 yang boleh meningkatkan keterlarutan BA dan kemudian kecekapannya untuk penghantaran ubat.

Kata kunci: CD-MOF, asid betulinik, mekanik kuantum, dok molekul, keterlarutan

References

1. Zhong, Y., Liang, N., Yang, L. and Cheng, M.-S. (2021). Recent progress on betulinic acid and its derivatives as antitumor agents: A mini-review. Chinese Journal of Natural Medicines, 19(9): 641-647.

2. Zhao, P., Guan, M., Tang, W., Walayat, N., Ding, Y. and Liu, J. (2023). Structural diversity, fermentation production, bioactivities and applications of triterpenoids from several common medicinal fungi: Recent advances and future perspectives. Fitoterapia, 166 (1): 1-14.

3. Kozubek, M., Höhlich, L., Hoenke, S., Deigner, H.-P., Al-Harrasi, A. and Csuk, R. (2021). Apoptotic activity of substituted 3-O-acetyl-betulinic acid benzylamides. European Journal of Medicinal Chemistry Reports, 3(1): 1-8.

4. Azenha, I., Aniceto, J., Sequeira, S., Mendes, A. and Silva, C. (2020). Chromatographic separation of betulinic and oleanolic acids. Separation and Purification Technology, 235(1): 1-11.

5. Chen, C., Song, K., Zhang, Y., Chu, C., Fan, B., Song, Y., Huang, H. and Chen, G. (2021). Biotransformation of betulinic acid by Circinella muscae and Cunninghamella echinulata to discover anti-inflammatory derivatives. Phytochemistry, 182(1): 1-7.

6. Bravo-Alfaro, D. A., Ochoa-Rodríguez, L. R., Villaseñor-Ortega, F., Luna-Barcenas, G. and García, H. S. (2022). Self-nano emulsifying drug delivery system (SNEDDS) improves the oral bioavailability of betulinic acid. Journal of Molecular Liquids, 364(1): 1-12.

7. Pokornı, J., Olejníková, D., Frydrych, I., Lišková, B., Gurská, S., Benická, S., Šarek, J., Kotulová, J., Hajdúch, M., & Džubák, P. (2021). Substituted dienes prepared from betulinic acid–Synthesis, cytotoxicity, mechanism of action, and pharmacological parameters. European Journal of Medicinal Chemistry, 224(1): 1-18.

8. Pisha, E., Chai, H., Lee, I.-S., Chagwedera, T. E., Farnsworth, N. R., Cordell, G. A., Beecher, C. W., Fong, H. H., Kinghorn, A. D. and Brown, D. M. (1995). Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nature medicine, 1(10): 1046-1051.

9. Jiang, W., Liu, H., Liao, Q., Tang, T., Liu, J., Liu, Z., Xie, L. and Yan, J. (2021). Preparation of two metal-organic frameworks (K-β-CD-MOFs and Cs-β-CD-MOFs) and the adsorption research of myricetin. Polyhedron, 196(1): 1-9.

10. Nicolov, M., Ghiulai, R. M., Voicu, M., Mioc, M., Duse, A. O., Roman, R., Ambrus, R., Zupko, I., Moaca, E. A. and Coricovac, D. E. (2019). Cocrystal formation of betulinic acid and ascorbic acid: Synthesis, physico-chemical assessment, antioxidant, and antiproliferative activity. Frontiers in Chemistry, 7(92): 1-11.

11. Zheng, L.-y., Zou, X., Wang, Y.-l., Zou, M., Ma, F., Wang, N., Li, J.-w., Wang, M.-s., Hung, H.-Y. and Wang, Q. (2022). Betulinic acid-nucleoside hybrid prevents acute alcohol-induced liver damage by promoting anti-oxidative stress and autophagy. European Journal of Pharmacology, 914(1): 1-13.

12. Boryczka, S., Bebenek, E., Jastrzebska, M., Kusz, J. and Zubko, M. (2012). Crystal structure of betulinic acid-DMSO solvate. Zeitschrift für Kristallographie, 227(6): 379-384.

13. Kutkowska, J., Strzadala, L. and Rapak, A. (2021). Hypoxia increases the apoptotic response to betulinic acid and betulin in human non-small cell lung cancer cells. Chemico-Biological Interactions, 333(1): 1-8.

14. Ghadi, R. and Dand, N. (2017). BCS class IV drugs: Highly notorious candidates for formulation development. Journal of Controlled Release, 248(1): 71-95.

15. Suresh, K., & Matzger, A. J. (2019). Enhanced drug delivery by the dissolution of amorphous drug encapsulated in a water unstable metal-organic framework (MOF). Angewandte Chemie International Edition, 58(47): 16790-16794.

16. Cheng, Z., Li, Y., Wang, K., Zhu, X., Tharkar, P., Shu, W., Zhang, T., Zeng, S., Zhu, L. and Murray, M. (2022). Compritol solid lipid nanoparticle formulations enhance the protective effect of betulinic acid derivatives in human Müller cells against oxidative injury. Experimental Eye Research, 215(1): 1-9.

17. Horvat, G., Pantić, M., Knez, Ž. and Novak, Z. (2018). Encapsulation and drug release of poorly water-soluble nifedipine from bio-carriers. Journal of Non-Crystalline Solids, 481(1): 486-493.

18. Li, H., Eddaoudi, M., O'Keeffe, M. and Yaghi, O. M. (1999). Design and synthesis of an exceptionally stable and highly porous metal-organic framework. Nature, 402(6759): 276-279.

19. Han, Z., Fan, X., Yu, S., Li, X., Wang, S. and Lu, L. (2022). Metal-organic frameworks (MOFs): A novel platform for laccase immobilization and application. Journal of Environmental Chemical Engineering, 10(1): 1-17.

20. Shan, Y., Zhang, G., Shi, Y. and Pang, H. (2023). Synthesis and catalytic application of defective MOF materials. Cell Reports Physical Science, 4(1): 1-44.

21. Haslina, A., Nur, A. Y., Khairulazhar, J. and Mohd, B. A. R. (2020). Ionothermal Synthesis of Zn-Based Metal-Organic Frameworks in Pyridinium Ionic Liquid. Malaysian Journal of Analytical Sciences, 24(2): 159-164.

22. Kamni, S. S., Kassim, K., Kassim, N. S. A. and Abidin, N. A. Z. (2021). Metal-organic frameworks as sorbent-based extraction: a review. Malaysian Journal of Analytical Sciences, 25(5): 791-807.

23. Balestri, D., Capucci, D., Demitri, N., Bacchi, A. and Pelagatti, P. (2017). Coordination-driven capture of nicotine inside a mesoporous MOF. Materials, 10(7): 1-12.

24. Hartlieb, K. J., Ferris, D. P., Holcroft, J. M., Kandela, I., Stern, C. L., Nassar, M. S., Botros, Y. Y. and Stoddart, J. F. (2017). Encapsulation of ibuprofen in CD-MOF and related bioavailability studies. Molecular Pharmaceutics, 14(5): 1831-1839.

25. Shen, M., Zhou, J., Elhadidy, M., Xianyu, Y., Feng, J., Liu, D. and Ding, T. (2022). Cyclodextrin metal-organic framework by ultrasound-assisted rapid synthesis for caffeic acid loading and antibacterial application. Ultrasonics Sonochemistry, 86(1): 1-10.

26. He, Y., Zhang, W., Guo, T., Zhang, G., Qin, W., Zhang, L., Wang, C., Zhu, W., Yang, M. and Hu, X. (2019). Drug nanoclusters formed in confined nano-cages of CD-MOF: dramatic enhancement of solubility and bioavailability of azilsartan. Acta Pharmaceutica Sinica B, 9(1): 97-106.

27. Zhou, Y., Zhao, Y., Niu, B., Luo, Q., Zhang, Y., Quan, G., Pan, X. and Wu, C. (2020). Cyclodextrin-based metal-organic frameworks for pulmonary delivery of curcumin with improved solubility and fine aerodynamic performance. International Journal of Pharmaceutics, 588(1): 1-8.

28. Mohammed, E.-R., EL FADILI, M., Mrabti, N. N., Zarougui, S. and Elhallaoui, M. (2022). QSAR, molecular docking, ADMET properties in silico studies for a series of 7-propanamide benzoxaboroles as potent anti-cancer agents. Chinese Journal of Analytical Chemistry, 50(12): 1-11.

29. Badran, A.-S. and Ibrahim, M. A. (2023). Synthesis, spectral characterization, DFT, and in silico ADME studies of the novel pyrido [1, 2-a] benzimidazoles and pyrazolo [3, 4-b] pyridines. Journal of Molecular Structure, 1274(1): 1-14.

30. Ibrahim, M. and Uzairu, A. (2023). 2D-QSAR, molecular docking, drug-likeness, and ADMET/pharmacokinetic predictions of some non-small cell lung cancer therapeutic agents. Journal of Taibah University Medical Sciences, 18(2): 295-309.

31. Sabu, V., Peter, J., Sasidharan Nair, A. I. B., Krishnan, S., Sathyaseelan Suja, L. P., Helen, A. and Radhakrishna Pillai, G. (2019). Combinatorial action of triterpenoid, flavonoid, and alkaloid on inflammation. Natural Product Communications, 14(8): 1-9.

32. Khan, M. F., Nahar, N., Rashid, R. B., Chowdhury, A. and Rashid, M. A. (2018). Computational investigations of physicochemical, pharmacokinetic, toxicological properties and molecular docking of betulinic acid, a constituent of Corypha taliera (Roxb.) with Phospholipase A2 (PLA2). BMC complementary and alternative medicine, 18(1): 1-15.

33. Malleda, C., Ahalawat, N., Gokara, M. and Subramanyam, R. (2012). Molecular dynamics simulation studies of betulinic acid with human serum albumin. Journal of Molecular Modeling, 18(1): 2589-2597.

34. Hohenberg, P. and Kohn, W. (1964). Inhomogeneous electron gas. Physical review, 136(3B): 1-8.

35. Kohn, W., and Sham, L. J. (1965). Self-consistent equations including exchange and correlation effects. Physical review, 140(4A): 1-6.

36. Rajaraman, D., Anthony, L. A., Nethaji, P. and Vallangi, R. (2023). One-pot synthesis, NMR, quantum chemical approach, molecular docking studies, drug-likeness and in-silico ADMET prediction of novel 1-(2, 3-dihydrobenzo [b][1, 4] dioxin-6-yl)-2-(furan-2-yl)-4, 5-diphenyl-1H-imidazole derivatives. Journal of Molecular Structure, 1273(1): 1-11.

37. Agwupuye, J. A., Gber, T. E., Edet, H. O., Zeeshan, M., Batool, S., Duke, O. E., Adah, P. O., Odey, J. O. and Egbung, G. E. (2023). Molecular modeling, DFT studies, and biological evaluation of methyl 2, 8-dichloro-1, 2-dihydroquinoline-3-carboxylate. Chemical Physics Impact, 6(1): 1-11.

38. O'Boyle, N. M., Banck, M., James, C. A., Morley, C., Vandermeersch, T. and Hutchison, G. R. (2011). Open Babel: An open chemical toolbox. Journal of Cheminformatics, 3(1): 1-14.

39. Yousefzadeh Borzehandani, M., Abdulmalek, E., Abdul Rahman, M. B. and Mohammad Latif, M. A. (2021). First-principles investigation of dimethyl-functionalized MIL-53 (Al) metal-organic framework for adsorption and separation of xylene isomers. Journal of Porous Materials, 28(2): 579-591.

40. Marenich, A. V., Cramer, C. J. and Truhlar, D. G. (2009). Universal solvation model based on solute electron density and a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. The Journal of Physical Chemistry B, 113(18): 6378-6396.

41. Muya, J. T., Mwanangombo, D. T., Tsalu, P. V., Mpiana, P. T., Tshibangu, D. S.-T., & Chung, H. (2019). Conceptual DFT study of the chemical reactivity of four natural products with anti-sickling activity. SN Applied Sciences, 1(1): 1-18.

42. Ayşen, I., Çevik, U. A., Çelik, I., Bostancı, H. E., Karayel, A., Gündoğdu, G., Ince, U., Koçak, A., Özkay, Y., & Kaplancıklı, Z. A. (2022). Benzimidazole-hydrazone derivatives: Synthesis, in vitro anticancer, antimicrobial, antioxidant activities, in silico DFT and ADMET studies. Journal of Molecular Structure, 1270(1): 1-10.

43. Smaldone, R. A., Forgan, R. S., Furukawa, H., Gassensmith, J. J., Slawin, A. M., Yaghi O. M. and Fraser, J. S. (2010). Metal-organic frameworks from edible natural products. Angewandte Chemie International Edition, 49(46): 8630-8634.