PTDP'nin Alzheimer Hastalığı Tedavisindeki Önemi: Kuantum Hesaplamaları, ADME Profili ve Moleküler Yerleştirme Yaklaşımları

Year 2025, Volume: 12 Issue: 2, 534 - 546, 30.11.2025

Ahmet Çağrı Ata , Barış Kartal , Aslıhan Aycan Tanrıverdi , Ümit Yıldıko

https://doi.org/10.35193/bseufbd.1641395

Abstract

Alzheimer hastalığı (AH), öğrenmeyi, hafızayı ve davranışı önemli ölçüde etkileyen yaşa bağlı nörodejeneratif bir beyin bozukluğudur. Bu çalışmada molekül, **N-fenil-5-(1H-pirol-2-il)-3-(p-tolil)-4,5-dihidro-1H-pirazol-1-karbotioamid (PTDP) **, AD için potansiyel bir inhibitör olarak değerlendirildi. Yoğunluk fonksiyonel teorisi (DFT) hesaplamaları, 6-311G(d,p) temel seti ile B3LYP ve B3PW91 fonksiyonel yöntemleri kullanılarak yapıldı. Termal özellikler, HOMO-LUMO enerji seviyeleri, dipol momenti, polarize edilebilirlik, kimyasal reaktivite tanımlayıcıları ve moleküler elektrostatik potansiyel (MEPS) gibi temel parametreler hesaplandı ve görselleştirildi. PTDP molekülü için enerji açığı (∆E), B3LYP yöntemiyle 3,603 eV ve B3PW91 yöntemiyle 3,977 eV olarak belirlendi ve bu, onun elektronik özellikleri ve reaktivitesi hakkında önemli bilgiler sağladı. Ek olarak, doğrusal olmayan optik (NLO) özellikler, işlevsel yönteme bağlı farklılıklar sergilerken, B3LYP hesaplaması yüksek bir x bileşeni dipol momenti (5,9430 D) gösterirken, B3PW91 yöntemi elektron yoğunluğu dağılımında daha fazla asimetri ortaya çıkardı. Bu bulgular PTDP'nin AD tedavisi ve NLO uygulamaları için potansiyelini göstermektedir. Moleküler yerleştirme sonuçları ayrıca PTDP'nin reseptör molekülüne karşı iyi bir bağlanma profiline sahip olduğunu gösterdi. İlaç keşfi ve geliştirilmesinde önemli olan ADMET analizi kullanılarak PTDP molekülünün farmakokinetik özellikleri de incelenmiştir. Ek olarak enerji çerçeveleri, moleküler yerleştirme sonuçları ve DFT hesaplaması yapıldı ve sonuçlar pirazol karbotiyoamid grubunun Alzheimer hastalığı (AD) aktivitesi için önemli olduğunu gösterdi.

Keywords

Alzheimer Hastalığı , DFT , Moleküler Modelleme , Pirazol

Importance of PTDP in Alzheimer's Disease Treatment: Quantum Calculations, ADME Profile, and Molecular Docking Approaches

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative brain disorder that significantly affects learning, memory, and behavior. In this study, molecule, **N-phenyl-5-(1H-pyrrol-2-yl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (PTDP)**, was evaluated as a potential inhibitor for AD. Density functional theory (DFT) calculations were performed using the B3LYP and B3PW91 functional methods with the 6-311G(d,p) basis set. Key parameters such as thermal properties, HOMO-LUMO energy levels, dipole moment, polarizability, chemical reactivity descriptors, and molecular electrostatic potential (MEPS) were computed and visualized. The energy gap (∆E) for the PTDP molecule was determined as 3.603 eV with the B3LYP method and 3.977 eV with the B3PW91 method, providing significant insights into its electronic properties and reactivity. Additionally, non-linear optical (NLO) properties demonstrated functional method-dependent variations, with the B3LYP calculation showing a high x-component dipole moment (5.9430 D), while the B3PW91 method revealed greater asymmetry in electron density distribution. These findings suggest PTDP's potential for AD treatment and NLO applications. Molecular docking results also showed that PTDP has a good binding profile towards the receptor molecule. Pharmacokinetic properties of the PTDP molecule were also examined using ADMET analysis, which is important in drug discovery and development. Additionally, energy frameworks, molecular docking results and DFT calculation were performed, and the results showed that the pyrazole carbothioamide group is important for Alzheimer's disease (AD) activity.

Keywords

Alzheimer Disease , DFT , Molecular Modelling , Pyrazole

References

• Santos, M. A., Chand, K., & Chaves, S. (2016). Recent progress in multifunctional metal chelators as potential drugs for Alzheimer's disease. Coordination Chemistry Reviews, 327, 287-303.
• Scheltens, P., Blennow, K., Breteler, M. M., De Strooper, B., Frisoni, G. B., Salloway, S., & Van der Flier, W. M. (2016). Alzheimer's disease. The Lancet, 388, 10043, 505-517.
• Kumar, D., Ganeshpurkar, A., Kumar, D., Modi, G., Gupta, S. K., & Singh, S. K. (2018). Secretase inhibitors for the treatment of Alzheimer's disease: Long road ahead. European journal of medicinal chemistry, 148, 436-452.
• Zhao, Q.-F., Tan, L., Wang, H.-F., Jiang, T., Tan, M.-S., Tan, L., Xu, W., Li, J.-Q., Wang, J., & Lai, T.-J. (2016). “The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis”: Corrigendum.
• Armstrong, R. A. (2019). Risk factors for Alzheimer’s disease. Folia neuropathologica, 57, 2, 87-105.
• Singh, A., Kukreti, R., Saso, L., & Kukreti, S. (2019). Oxidative stress: a key modulator in neurodegenerative diseases. Molecules, 24, 8, 1583.
• Scheltens, P., De Strooper, B., Kivipelto, M., Holstege, H., Chételat, G., Teunissen, C. E., Cummings, J., & van der Flier, W. M. (2021). Alzheimer's disease. The Lancet, 397, 10284, 1577-1590.
• Selkoe, D. J., & Hardy, J. (2016). The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO molecular medicine, 8, 6, 595-608.
• Sánchez Montero, J., González Matilla, J. F., Alcántara León, A. R., & Doadrio Villarejo, A. L. (2019). Developments with multi-target drugs for Alzheimer’s disease: an overview of the current discovery approaches.
• Mathew, B., Parambi, D. G., Mathew, G. E., Uddin, M. S., Inasu, S. T., Kim, H., Marathakam, A., Unnikrishnan, M. K., & Carradori, S. (2019). Emerging therapeutic potentials of dual‐acting MAO and AChE inhibitors in Alzheimer's and Parkinson's diseases. Archiv der Pharmazie, 352, 11, 1900177.
• Martins, P., Jesus, J., Santos, S., Raposo, L. R., Roma-Rodrigues, C., Baptista, P. V., & Fernandes, A. R. (2015). Heterocyclic anticancer compounds: recent advances and the paradigm shift towards the use of nanomedicine’s tool box. Molecules, 20, 9, 16852-16891.
• Hosseini, H., & Bayat, M. (2018). Cyanoacetohydrazides in synthesis of heterocyclic compounds. Topics in Current Chemistry, 376, 1-67.
• Musiol, R. (2017). An overview of quinoline as a privileged scaffold in cancer drug discovery. Expert Opinion on Drug Discovery, 12, 6, 583-597.
• Shah, R., & Verma, P. K. (2018). Therapeutic importance of synthetic thiophene. Chemistry Central Journal, 12, 1-22.
• Al-Hazmy, S. M., Zouaghi, M. O., Amri, N., Arfaoui, Y., Alhagri, I. A., & Hamdi, N. (2023). DFT Study of Regio-and Stereoselective 13DC Reaction between Diazopropane and Substituted Chalcone Derivatives: Molecular Docking of Novel Pyrazole Derivatives as Anti-Alzheimer’s Agents. Molecules, 28, 4, 1899.
• Frisch, M., & Clemente, F. MJ Frisch, GW Trucks, HB Schlegel, GE Scuseria, MA Robb, JR Cheeseman, G. Scalmani, V. Barone, B. Mennucci, GA Petersson, H. Nakatsuji, M. Caricato, X. Li, HP Hratchian, AF Izmaylov, J. Bloino and G. Zhe, Gaussian, 9.
• Stephens, P. J., Devlin, F. J., Chabalowski, C. F., & Frisch, M. J. (1994). Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields. The Journal of physical chemistry, 98, 45, 11623-11627.
• Khairulah, A.-E., Shuhaib, Z. A., Alharis, R., & Hussein, K. (2024). Synthesis, Anticancer Activity, and Computational Studies of New Pyrazole Derivatives. Russian Journal of General Chemistry, 94, 3, 719-728.
• Gören, K., & Yıldıko, Ü. Aldose Reductase Evaluation against Diabetic Complications Using ADME and Molecular Docking Studies and DFT Calculations of Spiroindoline Derivative Molecule. Süleyman Demirel Üniversitesi Fen Bilimleri Enstitüsü Dergisi, 28, 2, 281-292.
• Gören, K., Bağlan, M., & Yıldıko, Ü. Melanoma Cancer Evaluation with ADME and Molecular Docking Analysis, DFT Calculations of (E)-methyl 3-(1-(4-methoxybenzyl)-2, 3-dioxoindolin-5-yl)-acrylate Molecule. Journal of the Institute of Science and Technology, 14, 3, 1186-1199.
• Matine, A., Es-Sounni, B., Bakhouch, M., Bahkali, A. H., El Alaoui El Abdallaoui, H., Wang, S., Syed, A., Wong, L. S., Saleh, N. i., & Zeroual, A. (2024). Design, synthesis, and evaluation of a pyrazole-based corrosion inhibitor: a computational and experimental study. Scientific Reports, 14, 1, 25238.
• Tahiroğlu, V., Gören, K., Bağlan, M., & Yıldıko, Ü. (2024). Molecular Docking and DFT Analysis of Thiazolidinone-Bis Schiff Base for anti-Cancer and anti-Urease Activity. Journal of the Institute of Science and Technology, 14, 2, 822-834, June.
• Gören, K., Bağlan, M., & Yıldıko, Ü. (2024). Melanoma Cancer Evaluation with ADME and Molecular Docking Analysis, DFT Calculations of (E)-methyl 3-(1-(4-methoxybenzyl)-2, 3-dioxoindolin-5-yl)-acrylate Molecule. Journal of the Institute of Science and Technology, 14, 3, 1186-1199.
• Bağlan, M., Yıldıko, Ü., & Gören, K. DFT CALCULATIONS AND MOLECULAR DOCKING STUDY IN 6-(2”-PYRROLIDINONE-5”-YL)-(-) EPICATECHIN MOLECULE FROM FLAVONOIDS. Eskişehir Teknik Üniversitesi Bilim ve Teknoloji Dergisi B-Teorik Bilimler, 11, 1, 43-55.
• Singh, V., Sharma, P., Sethi, O., Thakur, A., & Malik, A. Novel Synthesis, Molecular Docking, Dft, and in Vitro Studies of Pyrazole Derivatives. Molecular Docking, Dft, and in Vitro Studies of Pyrazole Derivatives.
• Dayananda, P., Nayak, J., Kudva, J., Chethan, D., & D'Souza, V. T. (2024). Synthesis, Characterization, Antimicrobial and DFT Studies of Novel Quinolino‐Pyrazole Derivatives. ChemistrySelect, 9, 32, e202401166.
• Brunt, K., Neumann, T., & Smith, B. (2019). Assessment of ICESat‐2 ice sheet surface heights, based on comparisons over the interior of the Antarctic ice sheet. Geophysical Research Letters, 46, 22, 13072-13078.
• Jahanshahi, A. A., Dinani, M. M., Madavani, A. N., Li, J., & Zhang, S. X. (2020). The distress of Iranian adults during the Covid-19 pandemic–More distressed than the Chinese and with different predictors. Brain, behavior, and immunity, 87, 124.
• Théry, C., Witwer, K. W., Aikawa, E., Alcaraz, M. J., Anderson, J. D., Andriantsitohaina, R., Antoniou, A., Arab, T., Archer, F., & Atkin‐Smith, G. K. (2018). Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. Journal of extracellular vesicles, 7, 1, 1535750.
• Klöwer, M., Allen, M., Lee, D., Proud, S., Gallagher, L., & Skowron, A. (2021). Quantifying aviation’s contribution to global warming. Environmental Research Letters, 16, 10, 104027.
• Brown, R., Rocha, A., & Cowling, M. (2020). <? covid19?> Financing entrepreneurship in times of crisis: exploring the impact of COVID-19 on the market for entrepreneurial finance in the United Kingdom. International Small Business Journal, 38, 5, 380-390.