AN IN SILICO PHARMACOKINETIC INVESTIGATION OF ORGANIC LUMINOGENS: UNDERSTANDING THE NIR AIEGENS AND THEIR INTERACTIONS WITH SERUM ALBUMINS

Öz

Objective: Fluorescence imaging (FLI) is accepted as a highly effective method for visualizing bioanalytics directly and gaining insight into complicated biological structures and processes. In this context, newly tailored organic molecules, which have the potential to be used in FLI, especially near-infrared (NIR) regions supported by aggregation-induced emission luminogens (AIEgens), are a rapidly developing area of study. Herein, using ADMET and molecular docking analyses, we examined the pharmacokinetic properties of both model (D2-A2-D2) and newly designed (Dn-An-Dn) organic luminogens to interact with blood proteins, namely bovine serum albumin (BSA) and human serum albumin (HSA), which have emerged as a versatile carrier of several therapeutic agents against preliminary cancer and infectious diseases. Material and Method: The structural properties of the examined luminogens were computed using the Gaussian 09 software package. The DFT/B3LYP/6-31G(d,p) level was then utilized for geometry optimization and accurately determining electronic structures and molecular properties. Lipinski's rule of five was applied to predict the drugability of the compounds using the SwissADME web tool. Molinspiration was used for further validation of these properties and additional bioactivity parameters. Toxicity parameters were evaluated with OSIRIS Property Explorer (v.4.5.1). Molecular docking simulations of the luminogen-albumin complexes were performed using SAMSON 2022 R2 modeling platform and implemented Autodock-vina extension. The X-ray crystal structures of bovine serum albumin (BSA, PDB ID: 4F5S) and human serum albumin (HSA, PDB ID: 4L9Q) were obtained from the Protein Data Bank. Visualization of the docking interactions was conducted using Discovery Studio Visualizer 2021. Result and Discussion: The compounds D1-A1-D1 and D1-A4-D1 stood out concerning molecular weight (MW) and ClogPo/w values, making them promising candidates for drug design. An analysis of lipophilicity revealed that these two compounds displayed high miLogP values, indicating a high degree of lipophilicity, which is generally beneficial for drug delivery. They also exhibited moderate bioactivity based on GPCR ligand and protease inhibitor (PI) parameters. On the other hand, D4-A3-D4 showcased paramount interaction with bovine serum albumin (BSA), while D5-A3-D5 demonstrated the highest binding affinity with human serum albumin (HSA).

Anahtar Kelimeler

• ADMET
• AIEgen
• BSA
• HSA
• molecular docking

ORGANİK LUMİNOJENLERİN İN SİLİKO FARMAKOKİNETİK İNCELENMESİ: NIR AIEJENLERİ VE SERUM ALBÜMİNLERİ İLE ETKİLEŞİMLERİNİ ANLAMAK

Öz

Amaç: Floresans görüntüleme (FLI), biyoanalitikleri doğrudan görselleştirme ve karmaşık biyolojik yapıları ve süreçleri anlamak için son derece etkili bir yöntem olarak kabul edilir. Bu bağlamda, özellikle agregasyon-indüklü emisyon luminojenleri (AIEjen) tarafından desteklenen ve yakın kızılötesi (NIR) bölgede kullanılma potansiyeli olan yeni özelleştirilmiş organik moleküller, hızla gelişen bir çalışma alanıdır. Bu noktada, ADMET ve moleküler kenetlenme analizlerini kullanarak, hem model (D2-A2-D2) hem de yeni tasarlanmış (Dn-An-Dn) organik luminogenlerin kan proteinleri ile etkileşme özelliklerini farmakokinetik açıdan inceledik. Bu kan proteinleri, özellikle sığır serum albumini (BSA) ve insan serum albumini (HSA), erken kanser ve bulaşıcı hastalıklarla mücadelede çeşitli terapötik ajanların taşıyıcısı olarak öne çıkmıştır. Gereç ve Yöntem: İncelenen luminojenlerin yapısal özellikleri Gaussian 09 yazılım paketi kullanılarak hesaplandı. Daha sonra DFT/B3LYP/6-31G(d,p) seviyesi, geometri optimizasyonu ve elektronik yapıların ve moleküler özelliklerin doğru bir şekilde belirlenmesi için kullanıldı. Bileşiklerin ilaçlaştırılabilirliğini tahmin etmek için Lipinski'nin beşli kuralı SwissADME web aracı kullanılarak uygulandı. Bu özelliklerin ve ek biyoaktivite parametrelerinin daha fazla doğrulanması için Molinspiration kullanıldı. Toksisite parametreleri OSIRIS Property Explorer (v.4.5.1) ile değerlendirildi. Luminojen-albümin komplekslerinin moleküler kenetlenme simülasyonları SAMSON 2022 R2 modelleme platformu ve Autodock-vina uzantısı kullanılarak gerçekleştirildi. Sığır serum albümininin (BSA, PDB ID: 4F5S) ve insan serum albümininin (HSA, PDB ID: 4L9Q) X-ışını kristal yapıları Protein Data Bank'tan alındı. Bağlanma etkileşimlerinin görselleştirilmesi Discovery Studio Visualizer 2021 kullanılarak gerçekleştirildi. Sonuç ve Tartışma: D1-A1-D1 ve D1-A4-D1 bileşikleri, moleküler ağırlık (MA) ve ClogPo/w değerleri açısından öne çıkarak onları ilaç tasarımı için umut verici adaylar haline getirdi. Lipofilisite analizi, bu iki bileşiğin yüksek miLogP değerleri gösterdiğini ortaya çıkardı ki bu genellikle ilaç taşınım için istenen yüksek derecede lipofilikliğe işaret etmektedir. Ayrıca bu bileşikler, GPCR ligandı ve proteaz inhibitörü (PI) parametrelerine dayalı olarak da orta düzeyde biyoaktivite sergilediler. Öte yandan D4-A3-D4, sığır serum albümini (BSA) ile olağanüstü etkileşim sergilerken, D5-A3-D5, insan serum albümini (HSA) ile en yüksek bağlanma afinitesini gösterdi.

Anahtar Kelimeler

• ADMET
• AIEjen
• BSA
• HSA
• moleküler kenetlenme

Kaynakça

1. 1. Park, J.W., Han, J.W. (2019). Targeting epigenetics for cancer therapy. Archives of Pharmacal Research, 42(2), 159-170. [CrossRef]
2. 2. Schuster, E., Taftaf, R., Reduzzi, C., Albert, M.K., Romero-Calvo, I., Liu, H. (2021). Better together: Circulating tumor cell clustering in metastatic cancer. Trends in Cancer, 7(11), 1020-1032. [CrossRef]
3. 3. Pucci, C., Martinelli, C., Ciofani, G. (2019). Innovative approaches for cancer treatment: Current perspectives and new challenges. Ecancermedicalscience, 13, 961. [CrossRef]
4. 4. Tokumaru, Y., Joyce, D., Takabe, K. (2020). Current status and limitations of immunotherapy for breast cancer. Surgery, 167(3), 628-630. [CrossRef]
5. 5. Yu, L.Y., Tang, J., Zhang, C.M., Zeng, W.J., Yan, H., Li, M.P., Chen, X.P. (2017). New immunotherapy strategies in breast cancer. International Journal of Environmental Research and Public Health, 14(1), 68. [CrossRef]
6. 6. Chilakamarthi, U., Giribabu, L. (2017). Photodynamic therapy: Past, present and future. Chemical Record, 17(8), 775-802. [CrossRef]
7. 7. Kroschinsky, F., Stölzel, F., von Bonin, S., Beutel, G., Kochanek, M., Kiehl, M., Schellongowski, P. (2017). New drugs, new toxicities: Severe side effects of modern targeted and immunotherapy of cancer and their management. Critical Care, 21(1), 89. [CrossRef]
8. 8. Oun, R., Moussa, Y.E., Wheate, N.J. (2018). The side effects of platinum-based chemotherapy drugs: A review for chemists. Dalton Transactions, 47(19), 6645-6653. [CrossRef]

9. 9. Dos Santos, A.F., De Almeida, D.R.Q., Terra, L.F., Baptista, M.S., Labriola, L. (2019). Photodynamic therapy in cancer treatment - an update review. Journal of Cancer Metastasis and Treatment, 5, 25. [CrossRef]
10. 10. Hamblin, M.R. (2020). Photodynamic therapy for cancer: What's past is prologue. Photochemistry and Photobiology, 96(3), 506-516. [CrossRef]
11. 11. Liu, S., Feng, G., Tang, B.Z., Liu, B. (2021). Recent advances of AIE light-up probes for photodynamic therapy. Chemical Science, 12(19), 6488-6506. [CrossRef]
12. 12. Wang, S., Wu, W., Manghnani, P., Xu, S., Wang, Y., Goh, C.C., Ng, L.G., Liu, B. (2019). Polymerization-enhanced two-photon photosensitization for precise photodynamic therapy. ACS Nano, 13(3), 3095-3105. [CrossRef]
13. 13. Plotino, G., Grande, N.M., Mercade, M. (2019). Photodynamic therapy in endodontics. International Endodontic Journal, 52(6), 760-774. [CrossRef]
14. 14. Gunaydin, G., Gedik, M.E., Ayan, S. (2021). Photodynamic therapy-current limitations and novel approaches. Frontiers in Chemistry, 9, 691697. [CrossRef]
15. 15. Li, X., Wu, J., Wang, L., He, C., Chen, L., Jiao, Y., Duan, C. (2020). Mitochondrial-DNA-targeted IrIII -containing metallohelices with tunable photodynamic therapy efficacy in cancer cells. Angewandte Chemie (International Ed. in English), 59(16), 6420-6427. [CrossRef]
16. 16. Wan, Q., Zhang, R., Zhuang, Z., Li, Y., Huang, Y., Wang, Z., Zhang, W., Hou, J., Tang, B.Z. (2020). Molecular engineering to boost aie-active free radical photogenerators and enable high-performance photodynamic therapy under hypoxia. Advanced Functional Materials, 30(39), 1-12. [CrossRef]
17. 17. Allison, R.R., Moghissi, K. (2013). Photodynamic therapy (PDT): PDT mechanisms. Clinical Endoscopy, 46(1), 24-29. [CrossRef]
18. 18. Filatov, M.A. (2020). Heavy-atom-free BODIPY photosensitizers with intersystem crossing mediated by intramolecular photoinduced electron transfer. Organic and Biomolecular Chemistry, 18(1), 10–27. [CrossRef]
19. 19. Li, X., Lee, D., Huang, J.D., Yoon, J. (2018). Phthalocyanine-assembled nanodots as photosensitizers for highly efficient type I photoreactions in photodynamic therapy. Angewandte Chemie International Edition, 57(31), 9885-9890. [CrossRef]
20. 20. Chinna Ayya Swamy, P., Sivaraman, G., Priyanka, R.N., Raja, S.O., Ponnuvel, K., Shanmugpriya, J., Gulyani, A. (2020). Near Infrared (NIR) absorbing dyes as promising photosensitizer for photo dynamic therapy. Coordination Chemistry Reviews, 411, 213233. [CrossRef]
21. 21. Li, Y., Cai, Z., Liu, S., Zhang, H., Wong, S.T.H., Lam, J.W.Y., Kwok, R.T.K., Qian, J., Tang, B.Z. (2020). Design of AIEgens for near-infrared IIb imaging through structural modulation at molecular and morphological levels. Nature Communications, 11(1), 1255. [CrossRef]
22. 22. Chen, Y., Xue, L., Zhu, Q., Feng, Y., Wu, M. (2021). Recent advances in second near-infrared region (NIR-II) fluorophores and biomedical applications. Frontiers in Chemistry, 9, 750404. [CrossRef]
23. 23. He, B., Situ, B., Zhao, Z., Zheng, L. (2020). Promising applications of AIEgens in animal models. Small Methods, 4(4), 1900583. [CrossRef]
24. 24. He, S., Song, J., Qu, J., Cheng, Z. (2018). Crucial breakthrough of second near-infrared biological window fluorophores: Design and synthesis toward multimodal imaging and theranostics. Chemical Society Reviews, 47(12), 4258-4278. [CrossRef]
25. 25. Anthony, S.P. (2012). Organic solid-state fluorescence: Strategies for generating switchable and tunable fluorescent materials. ChemPlusChem, 77(7), 518-531. [CrossRef]
26. 26. Li, X., Jiang, M., Li, Y., Xue, Z., Zeng, S., Liu, H. (2019). 808 nm laser-triggered NIR-II emissive rare-earth nanoprobes for small tumor detection and blood vessel imaging. Materials Science and Engineering C, 100, 260-268. [CrossRef]
27. 27. Kenry, Duan, Y., Liu, B. (2018). Recent advances of optical imaging in the second near-infrared window. Advanced Materials, 30(47), 1-19. [CrossRef]
28. 28. Hu, C., Guo, T., Li, H., Xu, P., Xiao, Y. (2021). A novel NIR-II probe for improved tumor-targeting NIR-II imaging. RSC Advances, 11(62), 39287-39290. [CrossRef]
29. 29. Luo, C., Sun, B., Wang, C., Zhang, X., Chen, Y., Chen, Q., Yu, H., Zhao, H., Sun, M., Li, Z., Zhang, H., Kan, Q., Wang, Y., He, Z., Sun, J. (2019). Self-facilitated ROS-responsive nanoassembly of heterotypic dimer for synergistic chemo-photodynamic therapy. Journal of Controlled Release, 302, 79-89. [CrossRef]
30. 30. Li, Y., Liu, S., Ni, H., Zhang, H., Zhang, H., Chuah, C., Ma, C., Wong, K.S., Lam, J.W.Y., Kwok, R.T.K., Qian, J., Lu, X., Tang, B.Z. (2020). ACQ‐to‐AIE transformation: Tuning molecular packing by regioisomerization for two‐photon NIR bioimaging. Angewandte Chemie, 132(31), 12922-12926. [CrossRef]
31. 31. Nie, H., Hu, K., Cai, Y., Peng, Q., Zhao, Z., Hu, R., Chen, J., Su, S.J., Qin, A., Tang, B.Z. (2017). Tetraphenylfuran: Aggregation-induced emission or aggregation-caused quenching? Materials Chemistry Frontiers, 1(6), 1125-1129. [CrossRef]
32. 32. Huang, Y., Xing, J., Gong, Q., Chen, L.C., Liu, G., Yao, C., Wang, Z., Zhang, H.L., Chen, Z., Zhang, Q. (2019). Reducing aggregation caused quenching effect through co-assembly of PAH chromophores and molecular barriers. Nature Communications, 10(1), 169. [CrossRef]
33. 33. Antaris, A.L., Chen, H., Cheng, K., Sun, Y., Hong, G., Qu, C., Diao, S., Deng, Z., Hu, X., Zhang, B., Zhang, X., Yaghi, O.K., Alamparambil, Z.R., Hong, X., Cheng, Z., Dai, H. (2016). A small-molecule dye for NIR-II imaging. Nature Materials, 15(2), 235-242. [CrossRef]
34. 34. Nguyen, V.N., Yan, Y., Zhao, J., Yoon, J. (2021). Heavy-atom-free photosensitizers: From molecular design to applications in the photodynamic therapy of cancer. Accounts of Chemical Research, 54(1), 207–220. [CrossRef]
35. 35. Xu, W., Wang, D., Tang, B.Z. (2020). NIR‐II AIEgens: A win win integration towards bioapplications. Angewandte Chemie International Edition, 60(14), 7476-7487. [CrossRef]
36. 36. Xu, P., Kang, F., Yang, W., Zhang, M., Dang, R., Jiang, P., Wang, J. (2020). Molecular engineering of a high quantum yield NIR-II molecular fluorophore with aggregation-induced emission (AIE) characteristics for: In vivo imaging. Nanoscale, 12(8), 5084-5090. [CrossRef]
37. 37. Bhasikuttan, A.C., Mohanty, J., Nau, W.M., Pal, H. (2007). Efficient fluorescence enhancement and cooperative binding of an organic dye in a supra-biomolecular host–protein assembly. Angewandte Chemie International Edition, 46(22), 4120-4122. [CrossRef]
38. 38. Anees, P., Sreejith, S., Ajayaghosh, A. (2014). Self-assembled near-infrared dye nanoparticles as a selective protein sensor by activation of a dormant fluorophore. Journal of the American Chemical Society, 136(38), 13233-13239. [CrossRef]
39. 39. Jameson, L.P., Smith, N.W., Annunziata, O., Dzyuba, S.V. (2016). Interaction of BODIPY dyes with bovine serum albumin: A case study on the aggregation of a click-BODIPY dye. Physical Chemistry Chemical Physics, 18(21), 14182-14185. [CrossRef]
40. 40. Schneider, F., Ruhlandt, D., Gregor, I., Enderlein, J., Chizhik, A.I. (2017). Quantum yield measurements of fluorophores in lipid bilayers using a plasmonic nanocavity. The Journal of Physical Chemistry Letters, 8(7), 1472-1475. [CrossRef]
41. 41. Alifu, N., Zebibula, A., Qi, J., Zhang, H., Sun, C., Yu, X., Xue, D., Lam, J.W.Y., Li, G., Qian, J., Tang, B. Z. (2018). Single-molecular near-infrared-ii theranostic systems: Ultrastable aggregation-induced emission nanoparticles for long-term tracing and efficient photothermal therapy. ACS Nano, 12(11), 11282-11293. [CrossRef]
42. 42. Qi, J., Sun, C., Zebibula, A., Zhang, H., Kwok, R.T.K., Zhao, X., Xi, W., Lam, J.W.Y., Qian, J., Tang, B.Z. (2018). Real-time and high-resolution bioimaging with bright aggregation-induced emission dots in short-wave infrared region. Advanced Materials, 30(12), 1706856. [CrossRef]
43. 43. Qian, G., Zhong, Z., Luo, M., Yu, D., Zhang, Z., Ma, D., Wang, Z.Y. (2009). Synthesis and application of thiadiazoloquinoxaline-containing chromophores as dopants for efficient near-infrared organic light-emitting diodes. The Journal of Physical Chemistry C, 113(4), 1589-1595. [CrossRef]
44. 44. Moriguchi, I., Hirono, S., Nakagome, I., Hirano, H. (1994). Comparison of reliability of log p values for drugs calculated by several methods. Chemical and Pharmaceutical Bulletin, 42(4), 976-978. [CrossRef]
45. 45. Lipinski, C.A., Lombardo, F., Dominy, B.W., Feeney, P.J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 46(1-3), 3-26. [CrossRef]
46. 46. Daina, A., Michielin, O., Zoete, V. (2017). SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7(1), 42717. [CrossRef]
47. 47. Ertl, P., Rohde, B., Selzer, P. (2000). Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. Journal of Medicinal Chemistry, 43(20), 3714-3717. [CrossRef]
48. 48. Coimbra, J.T.S., Feghali, R., Ribeiro, R.P., Ramos, M.J., Fernandes, P.A. (2020). The importance of intramolecular hydrogen bonds on the translocation of the small drug piracetam through a lipid bilayer. RSC Advances, 11(2), 899-908. [CrossRef]
49. 49. Khan, T., Dixit, S., Ahmad, R., Raza, S., Azad, I., Joshi, S., Khan, A.R. (2017). Molecular docking, PASS analysis, bioactivity score prediction, synthesis, characterization and biological activity evaluation of a functionalized 2-butanone thiosemicarbazone ligand and its complexes. Journal of Chemical Biology, 10(3), 91-104. [CrossRef]
50. 50. Dilly, S., Lamy, C., Marrion, N. V., Liégeois, J. F., Seutin, V. (2011). Ion-Channel Modulators: More diversity than previously thought. ChemBioChem, 12(12), 1808-1812. [CrossRef]
51. 51. Ferguson, F.M., Gray, N.S. (2018). Kinase inhibitors: The road ahead. Nature Reviews Drug Discovery, 17(5), 353-376. [CrossRef]
52. 52. Fischer, A., Smieško, M. (2019). Ligand pathways in nuclear receptors. Journal of Chemical Information and Modeling, 59(7), 3100-3109. [CrossRef]
53. 53. Puratchikody, A., Sriram, D., Umamaheswari, A., Irfan, N. (2016). 3-D structural interactions and quantitative structural toxicity studies of tyrosine derivatives intended for safe potent inflammation treatment. Chemistry Central Journal, 10(1), 1-19. [CrossRef]