TY  - JOUR
T1  - Pektolinarigenin'in Antioksidan Aktivitesi: DFT Çalışmaları, Hirshfeld Yüzey Analizi, Moleküler Kenetleme Araştırması ve ADME/T Tahmini
TT  - Antioxidant Activity of Pectolinarigenin: DFT Studies, Hirshfeld Surface Analysis, Molecular Docking Investigation and ADME/T Prediction
AU  - Göcen, Tugba
PY  - 2025
DA  - October
Y2  - 2025
DO  - 10.35414/akufemubid.1641818
JF  - Afyon Kocatepe Üniversitesi Fen Ve Mühendislik Bilimleri Dergisi
PB  - Afyon Kocatepe Üniversitesi
WT  - DergiPark
SN  - 2149-3367
SP  - 1018
EP  - 1031
VL  - 25
IS  - 5
LA  - tr
AB  - Pektolinarigenin’in (5,7-dihidroksi-6,4'-dimetoksiflavon) potansiyel bir antioksidan ilaç adayı olarak değerlendirilmesi amacıyla moleküler yapı parametreleri, elektronik ve kimyasal reaktivite tanımlayıcıları belirlemek için yoğunluk fonksiyoneli teorisi (DFT) kullanılanılarak hesaplanmıştır. B3LYP/6-311G(d,p) baz seti ile optimize edilen moleküler yapı, literatürde rapor edilen X-ışını kristal yapısı ile karşılaştırılmıştır. Ayrıca, kristal yapısındaki moleküller arası etkileşimler, üç boyutlu Hirshfeld yüzeyi ve iki boyutlu parmak izi çizimleri ile görselleştirilmiştir. Molekülün elektrostatik potansiyel haritası (MEP), sınır moleküler orbitalleri (FMOs) ve Mulliken atomik yükleri hesaplanarak kimyasal olarak aktif bölgeler belirlenmiştir. Ek olarak, Pektolinarigenin’in vücudun antioksidan savunma sisteminin aktivasyonunda rol oynayan NADPH oksidaz enzimi (PDB ID: 2CDU) ile afinitesini değerlendirmek amacıyla moleküler kenetleme çalışması yapılmıştır. Bu analizler, Pektolinarigenin’in hedef proteinin aktif bölgesiyle güçlü bir etkileşim gösterdiğini ve -8.5 kcal/mol bağlanma enerjisiyle yüksek bir bağlanma afinitesine sahip olduğunu ortaya koymuştur. Ayrıca, farmakokinetik özellikler ve ilaç benzerliği analizleri, Pektolinarigenin’in antioksidan ilaç olarak geliştirilmesi için uygun bir aday olduğunu göstermektedir.
KW  - Flavonoid
KW  - DFT
KW  - Antioksidan
KW  - Hirshfeld yüzey analizi
KW  - Moleküler kenetleme
KW  - ADMET
N2  - Pectolinarigenin (5,7-dihydroxy-6,4'-dimethoxyflavone) has been investigated as a potential antioxidant drug candidate by determining its molecular structure parameters, electronic properties, and chemical reactivity descriptors using density functional theory (DFT). The molecular structure was optimized at the B3LYP/6-311G(d,p) level and compared with the X-ray crystal structure reported in the literature. Furthermore, intermolecular interactions in the crystal structure were visualized through three-dimensional Hirshfeld surface analysis and two-dimensional fingerprint plots. The molecular electrostatic potential (MEP) map, frontier molecular orbitals (FMOs), and Mulliken atomic charges were calculated to identify chemically active regions. Additionally, a molecular docking study was conducted to assess the binding affinity of Pectolinarigenin to NADPH oxidase (PDB ID: 2CDU), an enzyme involved in the activation of the body's antioxidant defense system. The results revealed that Pectolinarigenin exhibits strong interactions with the active site of the target protein and possesses a high binding affinity with a binding energy of -8.5 kcal/mol. Moreover, pharmacokinetic property analysis and drug-likeness evaluations indicate that Pectolinarigenin is a promising candidate for development as an antioxidant drug.
CR  - Ahmad, M. N., Karim, N. U., Normaya, E., Mat Piah, B., Iqbal, A., & Ku Bulat, K. H. (2020). Artocarpus altilis extracts as a food-borne pathogen and oxidation inhibitors: RSM, COSMO RS, and molecular docking approaches. Scientific Reports, 10(1), 9566. 
https://doi.org/10.1038/s41598-020-66488-7
CR  - Aitha, S., Thumma, V., Matta, R., Ambala, S., Jyothi, K., Manda, S., & Pochampally, J. (2023). Antioxidant activity of novel 4H- chromene tethered 1,2,3-Triazole Analogues: Synthesis and molecular docking studies. Results in Chemistry, 5, 100987. 
https://doi.org/10.1016/j.rechem.2023.100987
CR  - Akintemi, E. O., Govender, K. K., & Singh, T. (2022). A DFT study of the chemical reactivity properties, spectroscopy and bioactivity scores of bioactive flavonols. Computational and Theoretical Chemistry, 1210, 113658.
https://doi.org/10.1016/j.comptc.2022.113658
CR  - Alkorta, I., & Perez, J. J. (1996). Molecular polarization potential maps of the nucleic acid bases. International Journal of Quantum Chemistry, 57(1), 123–135. 
https://doi.org/10.1002/(SICI)1097-461X(1996)57:1 <123::AID-QUA14>3.0.CO;2-9
CR  - Arfin, S., Jha, N. K., Jha, S. K., Kesari, K. K., Ruokolainen, J., Roychoudhury, S., Rathi, B., & Kumar, D. (2021). Oxidative Stress in Cancer Cell Metabolism. Antioxidants, 10(5), 642. 
https://doi.org/10.3390/antiox10050642
CR  - Bahrun, Okino, T., Rasyid, H., & Soekamto, N. H. (2023). Biological evaluation and molecular docking of Indonesian Gracilaria salicornia as antioxidant agents. Journal of Research in Pharmacy, 27(1), 207–220. 
https://doi.org/10.29228/jrp.304
CR  - Bedard, K., & Krause, K.-H. (2007). The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology. Physiological Reviews, 87(1), 245–313. 
https://doi.org/10.1152/physrev.00044.2005
CR  - BIOVIA, D. S. (2012). BIOVIA Discovery Studio Visualizer - Dassault Systèmes. Computational Molecular Bioscience.
CR  - Bouayed, J., & Bohn, T. (2010). Exogenous Antioxidants—Double‐Edged Swords in Cellular Redox State: Health Beneficial Effects at Physiologic Doses versus Deleterious Effects at High Doses. Oxidative Medicine and Cellular Longevity, 3(4), 228–237. https://doi.org/10.4161/oxim.3.4.12858
CR  - Braga, E., Marinho, M. M., Marinho, E. S., Braga, E. J., Corpe, B. T., & Machado Marinho, M. (2016). Molecular electrostatic potential surface, HOMO–LUMO,  and computational analysis of synthetic drug Rilpivirine. Article in International Journal of Scientific and Engineering Research, 7(7), 315. http://www.ijser.org
CR  - Chen, L., Wei, Y., Zhao, S., Zhang, M., Yan, X., Gao, X., Li, J., Gao, Y., Zhang, A., & Gao, Y. (2018). Antitumor and immunomodulatory activities of total flavonoids extract from persimmon leaves in H22 liver tumor-bearing mice. Scientific Reports, 8(1), 10523. https://doi.org/10.1038/s41598-018-28440-8
CR  - Cheriet, T., Ben-Bachir, B., Thamri, O., Seghiri, R., & Mancini, I. (2020). Isolation and Biological Properties of the Natural Flavonoids Pectolinarin and Pectolinarigenin—A Review. Antibiotics, 9(7), 417. https://doi.org/10.3390/antibiotics9070417
CR  - Chocry, M., & Leloup, L. (2020). The NADPH Oxidase Family and Its Inhibitors. Antioxidants & Redox Signaling, 33(5), 332–353. https://doi.org/10.1089/ars.2019.7915
CR  - Cushnie, T. P. T., & Lamb, A. J. (2011). Recent advances in understanding the antibacterial properties of flavonoids. International Journal of Antimicrobial Agents, 38(2), 99–107. https://doi.org/10.1016/j.ijantimicag.2011.02.014
CR  - 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. https://doi.org/10.1038/srep42717
CR  - Dennington, R., Keith, T. A. ., & Millam, J. M. (2016). GaussView 6. In Gaussian.
Devadasu, V. R., Deb, P. K., Maheshwari, R., Sharma, P., & Tekade, R. K. (2018). Physicochemical, Pharmaceutical, and Biological Considerations in GIT Absorption of Drugs. In Dosage Form Design Considerations (pp. 149–178). Elsevier. https://doi.org/10.1016/B978-0-12-814423-7.00005-8
CR  - Dhaouadi, Z., Nsangou, M., Garrab, N., Anouar, E. H., Marakchi, K., & Lahmar, S. (2009). DFT study of the reaction of 
quercetin with and radicals. Journal of Molecular Structure: THEOCHEM, 904(1–3), 35–42. 
https://doi.org/10.1016/j.theochem.2009.02.034
CR  - Dita Arviana, S., Yueniwati, Y., Rahayu, M., & Rizki Syaban, M. F. (2022). 7,8-dihydroxyflavone as a Neuroprotective agent in Ischemic Stroke through the Regulation of HIF-1α Protein. Research Journal of Pharmacy and Technology, 3980–3986. 
https://doi.org/10.52711/0974-360X.2022.00667
CR  - Ferraz, C. R., Carvalho, T. T., Manchope, M. F., Artero, N. A., Rasquel-Oliveira, F. S., Fattori, V., Casagrande, R., & Verri, W. A. (2020). Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development. Molecules, 25(3), 762. 
https://doi.org/10.3390/molecules25030762
CR  - Frisch, M. J., Trucks, G. W., & H. B. Schlegel. (2016). Gaussian 16, Revision C.01. Gaussian. In Inc.: Wallingford CT.
Harborne, J. B., & Williams, C. A. (2000). Advances in flavonoid research since 1992. In Phytochemistry. 
https://doi.org/10.1016/S0031-9422(00)00235-1
CR  - Hayes, J. D., Dinkova-Kostova, A. T., & Tew, K. D. (2020). Oxidative Stress in Cancer. In Cancer Cell. 
https://doi.org/10.1016/j.ccell.2020.06.001
CR  - Izzo, C., Vitillo, P., Di Pietro, P., Visco, V., Strianese, A., Virtuoso, N., Ciccarelli, M., Galasso, G., Carrizzo, A., & Vecchione, C. (2021). The Role of Oxidative Stress in Cardiovascular Aging and Cardiovascular Diseases. Life, 11(1), 60. 
https://doi.org/10.3390/life11010060
CR  - Jiao, X., Jin, X., Ma, Y., Yang, Y., Li, J., Liang, L., Liu, R., & Li, Z. (2021). A comprehensive application: Molecular docking and network pharmacology for the prediction of bioactive constituents and elucidation of mechanisms of action in component-based Chinese medicine. Computational Biology and Chemistry, 90, 107402. 
https://doi.org/10.1016/j.compbiolchem.2020.107402
CR  - Justino, G. C., & Vieira, A. J. S. C. (2010). Antioxidant mechanisms of quercetin and myricetin in the gas phase and in solution- A comparison and validation of semi-empirical methods. Journal of Molecular Modeling. 
https://doi.org/10.1007/s00894-009-0583-1
CR  - Kabel, A. M., Omar, M. S., Alhadhrami, A., Alharthi, S. S., & Alrobaian, M. M. (2018). Linagliptin potentiates the effect of l-dopa on the behavioural, biochemical and immunohistochemical changes in experimentally-induced Parkinsonism: Role of toll-like receptor 4, TGF-β1, NF-κB and glucagon-like peptide 1. Physiology & Behavior, 188, 108–118. 
https://doi.org/10.1016/j.physbeh.2018.01.028
CR  - Karelson, M., Lobanov, V. S., & Katritzky, A. R. (1996). Quantum-chemical descriptors in QSAR/QSPR studies. Chemical Reviews. 96 (3), 1027-1044.
https://doi.org/10.1021/cr950202r
CR  - Kim, G. H., Kim, J. E., Rhie, S. J., & Yoon, S. (2015). The Role of Oxidative Stress in Neurodegenerative Diseases. In Experimental Neurobiology. 24(4): 325-340.
https://doi.org/10.5607/en.2015.24.4.325
CR  - Lameira, J., Alves, C. N., Santos, L. S., Santos, A. S., de Almeida Santos, R. H., Souza, J., Silva, C. C., & da Silva, A. B. F. (2008). A combined X-ray and theoretical study of flavonoid compounds with anti-inflammatory activity. Journal of Molecular Structure: THEOCHEM, 862(1–3), 16–20. 
https://doi.org/10.1016/j.theochem.2008.04.029
CR  - Liguori, I., Russo, G., Curcio, F., Bulli, G., Aran, L., Della-Morte, D., Gargiulo, G., Testa, G., Cacciatore, F., Bonaduce, D., & Abete, P. (2018). Oxidative stress, aging, and diseases. In Clinical Interventions in Aging, 13, 757—772. 
https://doi.org/10.2147/CIA.S158513
CR  - 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
CR  - Liskova, A., Koklesova, L., Samec, M., Smejkal, K., Samuel, S. M., Varghese, E., Abotaleb, M., Biringer, K., Kudela, E., Danko, J., Shakibaei, M., Kwon, T. K., Büsselberg, D., & Kubatka, P. (2020). Flavonoids in cancer metastasis. Cancers, 12(6), 1498. 
https://doi.org/10.3390/cancers12061498
CR  - Liu, Y., Yang, X., Gan, J., Chen, S., Xiao, Z.-X., & Cao, Y. (2022). CB-Dock2: improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting. Nucleic Acids Research, 50(W1), W159–W164. 
https://doi.org/10.1093/nar/gkac394
CR  - Martins, H. F. P., Leal, J. P., Fernandez, M. T., Lopes, V. H. C., & Cordeiro, M. N. D. S. (2004). Toward the prediction of the activity of antioxidants: Experimental and theoretical study of the gas-phase acidities of flavonoids. Journal of the American Society for Mass Spectrometry, 5 (6), 848-861. 
https://doi.org/10.1016/j.jasms.2004.02.007
CR  - Mhya, D. H., Jakwa, A. G., & Agbo, J. (2023). In Silico Analysis of Antioxidant Phytochemicals with Potential NADPH Oxidase Inhibitory Effect. Journal of Health Science and Medical Research, 41(2), 1–16. 
https://doi.org/10.31584/jhsmr.2022912
CR  - Møller, P., Wallin, H., & Knudsen, L. E. (1996). Oxidative stress associated with exercise, psychological stress and life-style factors. Chemico-Biological Interactions, 102(1), 17–36. 
https://doi.org/10.1016/0009-2797(96)03729-5
CR  - Mou, M.-Y., Pi, K., Zhang, Q.-L., Zhang, Y.-Q., & Zhang, Q.-J. (2008). 5,7-Dihydroxy-6,4′-dimethoxyflavone. Acta Crystallographica Section E Structure Reports Online, 64(1), o71. 
https://doi.org/10.1107/S160053680706179X
CR  - Nijveldt, R. J., Van Nood, E., Van Hoorn, D. E. C., Boelens, P. G., Van Norren, K., & Van Leeuwen, P. A. M. (2001). Flavonoids: A review of probable mechanisms of action and potential applications. In American Journal of Clinical Nutrition, Volume 74, 4, 418-425. 
https://doi.org/10.1093/ajcn/74.4.418
CR  - O’Boyle, N. M., Tenderholt, A. L., & Langner, K. M. (2008). Cclib: A library for package-independent computational chemistry algorithms. Journal of Computational Chemistry, 29: 839-845. 
https://doi.org/10.1002/jcc.20823
CR  - Pagadala, N. S., Syed, K., & Tuszynski, J. (2017). Software for molecular docking: a review. Biophysical Reviews, 9(2), 91–102. 
https://doi.org/10.1007/s12551-016-0247-1
CR  - Pantoja, L. V. P. da S., Trindade, S. S. A., Carneiro, A. da S., Silva, J. P. B., Paixão, T. P. da, Romeiro, C. F. R., Moraes, C. S. P. de, Pinto, A. C. G., Raposo, N. R. B., & Andrade, M. A. de. (2022). Computational study of the main flavonoids from Chrysobalanus icaco L. against NADPH-oxidase and in vitro Antioxidant Activity. Research, Society and Development, 11(6), e5011628542. 
https://doi.org/10.33448/rsd-v11i6.28542
CR  - Parr, R. G., Szentpály, L. V., & Liu, S. (1999). Electrophilicity Index. Journal of the American Chemical Society, 121(9), 1922–1924. 
https://doi.org/10.1021/ja983494x
CR  - Pearson, R. G. (1986). Absolute electronegativity and hardness correlated with molecular orbital theory. Proceedings of the National Academy of Sciences, 83(22), 8440–8441. 
https://doi.org/10.1073/pnas.83.22.8440
CR  - Pires, D. E. V., Blundell, T. L., & Ascher, D. B. (2015). pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. Journal of Medicinal Chemistry, 58(9), 4066–4072. 
https://doi.org/10.1021/acs.jmedchem.5b00104
CR  - Pisoschi, A. M., & Pop, A. (2015). The role of antioxidants in the chemistry of oxidative stress: A review. European Journal of Medicinal Chemistry, 97, 55–74. 
https://doi.org/10.1016/j.ejmech.2015.04.040
CR  - Pripdeevech, P., Chumpolsri, W., Suttiarporn, P., & Wongpornchai, S. (2010). The chemical composition and antioxidant activities of basil from Thailand using retention indices and comprehensive two-dimensional gas chromatography. Journal of the Serbian Chemical Society, 75, 11, 1503-1513. 
https://doi.org/10.2298/JSC100203125P
CR  - Rahaman, S. T., & Mondal, S. (2020). Flavonoids: A vital resource in healthcare and medicine. Pharmacy & Pharmacology International Journal, 8(2), 91–104. 
https://doi.org/10.15406/ppij.2020.08.00285
CR  - Rasul, H., Aziz, B., Morán, G., Mendoza-Huizar, L., Belhassan, A., Candia, L., Villada, W., & Sadasivam, K. (2023). A COMPUTATIONAL STUDY OF THE ANTIOXIDANT POWER OF EUGENOL COMPARED TO VITAMIN C. Química Nova, 46(9), 873–880. 
https://doi.org/10.21577/0100-4042.20230073
CR  - Sadasivam, K., & Kumaresan, R. (2011a). Theoretical investigation on the antioxidant behavior of chrysoeriol and hispidulin flavonoid compounds – A DFT study. Computational and Theoretical Chemistry, 963(1), 227–235. 
https://doi.org/10.1016/j.comptc.2010.10.025
CR  - Sadasivam, K., & Kumaresan, R. (2011b). Antioxidant behavior of mearnsetin and myricetin flavonoid compounds — A DFT study. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 79(1), 282–293. 
https://doi.org/10.1016/j.saa.2011.02.042
CR  - Sena, L. A., & Chandel, N. S. (2012). Physiological Roles of Mitochondrial Reactive Oxygen Species. Molecular Cell, 48(2), 158–167. 
https://doi.org/10.1016/j.molcel.2012.09.025
CR  - Spackman, M. A., & Jayatilaka, D. (2009). Hirshfeld surface analysis. CrystEngComm, 11(1), 19–32. 
https://doi.org/10.1039/B818330A
CR  - Spackman, P. R., Turner, M. J., McKinnon, J. J., Wolff, S. K., Grimwood, D. J., Jayatilaka, D., & Spackman, M. A. (2021). CrystalExplorer : a program for Hirshfeld surface analysis, visualization and quantitative analysis of molecular crystals. Journal of Applied Crystallography, 54(3), 1006–1011. 
https://doi.org/10.1107/S1600576721002910
CR  - Tajammal, A., Siddiqa, A., Irfan, A., Azam, M., Hafeez, H., Munawar, M. A., & Basra, M. A. R. (2022). Antioxidant, molecular docking and computational investigation of new flavonoids. Journal of Molecular Structure, 1254, 132189. 
https://doi.org/10.1016/j.molstruc.2021.132189
CR  - Tarafdar, A., & Pula, G. (2018). The Role of NADPH Oxidases and Oxidative Stress in Neurodegenerative Disorders. International Journal of Molecular Sciences, 19(12), 3824. 
https://doi.org/10.3390/ijms19123824
CR  - Tungmunnithum, D., Thongboonyou, A., Pholboon, A., & Yangsabai, A. (2018). Flavonoids and Other Phenolic Compounds from Medicinal Plants for Pharmaceutical and Medical Aspects: An Overview. Medicines, 5(3), 93. 
https://doi.org/10.3390/medicines5030093
CR  - Williams, R. J., Spencer, J. P. E., & Rice-Evans, C. (2004). Flavonoids: antioxidants or signalling molecules? Free Radical Biology & Medicine, 36(7), 838–849. 
https://doi.org/10.1016/j.freeradbiomed.2004.01.001
CR  - Yin, J., Heo, S.-I., & Wang, M.-H. (2008). Antioxidant and antidiabetic activities of extracts from Cirsium japonicum roots. Nutrition Research and Practice, 2(4):247-251. 
https://doi.org/10.4162/nrp.2008.2.4.247
CR  - Yueniwati, Y., Rizki Syaban, M. F., Kurniawan, D. B., Azam, A. A., Alvenia, D. M., Nur Savira, Y., Muhammad, R. F., Adnani, B., Violita, A. H., Arviana, S. D., Hasibuan, A., Norahmawati, E., Fatmasari, Y., Mufidah, A., Savitri, K. A., Zulfikri, U. R., Putri, D. Y., & Utami, S. (2024). 7,8‑Dihydroxyflavone functions as an antioxidant through the inhibition of Kelch‑like ECH‑associated protein 1: Molecular docking and an in vivo approach in a rat model of ischemia‑reperfusion brain injury. World Academy of Sciences Journal, 6: 15. 
https://doi.org/10.3892/wasj.2024.230
CR  - Zhan, C.-G., Nichols, J. A., & Dixon, D. A. (2003). Ionization Potential, Electron Affinity, Electronegativity, Hardness, and Electron Excitation Energy: Molecular Properties from Density Functional Theory Orbital Energies. The Journal of Physical Chemistry A, 107(20), 4184–4195. 
https://doi.org/10.1021/jp0225774
CR  - www.rcsb.org (24.04.2024)
CR  - http://cao.labshare.cn/cb-dock/ (30.05.2024)
UR  - https://doi.org/10.35414/akufemubid.1641818
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