SavedAdd your journal

Journals / European Journal of Life Sciences / 2025 / Volume: 4 Issue: 3

Computational insights into the chemical reactivity of Alzheimer’s therapeutics: a DFT-based study

Demokrat Nuha(University for Business and Technology (UBT))0000-0002-7271-6791
Halil Berber(ESKISEHIR TECHNICAL UNIVERSİTY)0000-0003-3869-3861
Ahmet Çağri Karaburun(ANADOLU UNIVERSITY)0000-0002-2503-3824
Pages
—
Publication Date
2025-12-31
🏛️Bibliographic metadata and full text access for this article are provided via DergiPark.
DergiPark Record ↗
✨

AI Summary & Key Takeaways

AI Insight
⚡ TL;DR(Too Long; Didn't Read)

Moreover, every compound assessed fulfilled Lipinski’s Rule of Five, indicating promising pharmacokinetic behavior and potential as orally active pharmaceutical candidates.

📌 3 Key Takeaways

🎯
Objective & Hypothesis:In this research, the structural and electronic characteristics, as well as the chemical reactivity of several therapeutic compounds employed in the management of Alzheimer’s disease, were examined through Density Functional Theory (DFT) analysis.
📊
Key Findings & Data:The molecular structures were optimized by applying the B3LYP functional together with the 6-31G(d,p) basis set.
💡
Conclusion & Impact:Moreover, every compound assessed fulfilled Lipinski’s Rule of Five, indicating promising pharmacokinetic behavior and potential as orally active pharmaceutical candidates.
🔬Design:Research Article
📍Scope:Comprehensive Sample
⚙️Variables:DFT · Chemical reactivity properties · Alzheimer

Abstract

In this research, the structural and electronic characteristics, as well as the chemical reactivity of several therapeutic compounds employed in the management of Alzheimer’s disease, were examined through Density Functional Theory (DFT) analysis. The molecular structures were optimized by applying the B3LYP functional together with the 6-31G(d,p) basis set. The obtained computational outcomes indicate that the analyzed molecules exhibit notable reactivity, especially in aqueous conditions, supporting their relevance for drug transport, considering the biological importance of water as a medium. To better understand the electronic nature of the molecules, atomic charge distributions were also evaluated, providing insight into their potential interactions with protein active sites. These findings help clarify the molecular basis of their inhibitory effects. Among all investigated agents, Donepezil demonstrated the highest level of chemical reactivity according to the calculated descriptors. Moreover, every compound assessed fulfilled Lipinski’s Rule of Five, indicating promising pharmacokinetic behavior and potential as orally active pharmaceutical candidates.

🔖

Cite This Article

Nuha, D., Berber, H., Karaburun, A. Ç. (2025). Computational insights into the chemical reactivity of Alzheimer’s therapeutics: a DFT-based study. European Journal of Life Sciences, Volume: 4 Issue: 3. https://doi.org/10.55971/EJLS.1705320

📄 Full Text PDF Viewer

📄

PDF görüntüleyici hazırlanıyor...

References (50)

  1. Matej R, Tesar A, Rusina R. Alzheimer’s disease and other neurodegenerative dementias in comorbidity: a clinical and neuropathological overview. Clin Biochem. (2019);73:26–31.
  2. Santiago JA, Potashkin JA. the impact of disease comorbidities in alzheimer’s disease. Front Aging Neurosci. (2021);13:631770.
  3. Prickaerts J, Heckman PRA, Blokland A. Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease. Expert Opin Investig Drugs. (2017);26(9):1033–1048.
  4. Giacobini E, Pepeu G. sex and gender differences in the brain cholinergic system and in the response to therapy of alzheimer disease with cholinesterase inhibitors. Curr Alzheimer Res. (2018);15(11):1077–1084.
  5. Galle SA, et al. the interrelationship between insulin-like growth factor 1, apolipoprotein E epsilon4, lifestyle factors, and the aging body and brain. J Prev Alzheimers Dis. (2020);7(4):265–273.
  6. Sampietro, A., Pérez-Areales, F. J., Martínez, P., Arce, E. M., Galdeano, C., Muñoz-Torrero, D. unveiling the multitarget anti-alzheimer drug discovery landscape: a bibliometric analysis. Pharmaceuticals. (2022);15(5).
  7. Agis-Torres A, Fernandez M, Sanchez-Montero JM. multi-target-directed ligands and other therapeutic strategies in the search of a real solution for alzheimer’s disease. Curr Neuropharmacol. (2014);12:2–36.
  8. Ding H., Zhang H., Ding H., Li D., Yi X., Ma X., Li R., Huang M., Ju X. Transplantation of placenta-derived mesenchymal stem cells reduces hypoxic-ischemic brain damage in rats by ameliorating the inflammatory response. Cell Mol Immunol. (2017);14(8):693–701.
  9. Çevik, U. A., Osmaniye, D., Sağlik, B. N., Çavuşoğlu, B. K., Levent, S., Karaduman, A. B., Ilgın., Karaburun AC., Özkay Y., Kaplancıklı Z.A., Turan, G. Multifunctional quinoxalinehydrazone derivatives with acetylcholinesterase and monoamine oxidases inhibitory activities as potential agents against Alzheimer’s disease. Med Chem Res. (2020);29(6):1000–1011.
  10. Kumar A, Singh A, Ekavali. A review on Alzheimer’s disease pathophysiology and its management: an update. Pharmacol Rep. (2015);67(2):195–203.
  11. Ulep MG, Saraon SK, McLea S. alzheimer disease. J Nurse Pract. (2018);14(3):129–135.
  12. Huang LK, Chao SP, Hu CJ. clinical trials of new drugs for alzheimer disease. J Biomed Sci. (2020);27(1):18.
  13. Singh, M., Kaur, M., Kukreja, H., Chugh, R., Silakari, O., Singh, D. Acetylcholinesterase inhibitors as Alzheimer therapy: from nerve toxins to neuroprotection. Eur J Med Chem. (2013);70:165–188.
  14. Matailo, A., Bec, N., Calva, J., Ramírez, J., Andrade, J. M., Larroque, C., Vidari G., Armijos, C. Selective BuChE inhibitory activity, chemical composition, and enantiomer content of the volatile oil from the Ecuadorian plant Clinopodium brownei. Rev Bras Farmacogn. (2019);29(6):749–754.
  15. Andrisano, V., Naldi, M., De Simone, A., Bartolini, M. A patent review of butyrylcholinesterase inhibitors and reactivators 2010–2017. Expert Opin Ther Pat. (2018);28(6):455–465.
  16. Minthon, L., Wallin, Å. K., Eriksson, S., Wattmo, C., Andreasen, N. Long-term rivastigmine treatment in a routine clinical setting. Acta Neurol Scand. (2009);119(3):180–185.
  17. Shin SJ, et al. Therapeutic effects of non-saponin fraction with rich polysaccharide from Korean red ginseng on aging and Alzheimer’s disease. Free Radic Biol Med. (2021);164:233–248.
  18. Sugimoto H, Yamada Y, Iimura Y, Kawakami Y. donepezil hydrochloride (E2020) and other acetylcholinesterase inhibitors. Curr Med Chem. (2000);7:303–339.
  19. Guan H, Sun H, Zhao X. application of density functional theory to molecular engineering of pharmaceutical formulations. Int J Mol Sci. (2025);26(7).
  20. Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Bolton, E. E. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res. (2021);49(D1):D1388–D1395.
  21. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, et al. Gaussian 09, Revision A.02. Gaussian, Inc., Wallingford, CT. (2016).
  22. Dennington R, Keith T, Millam J. GaussView, version 5. Semichem Inc. (2009).
  23. Becke AD. Density-functional thermochemistry. I. the effect of the exchange-only gradient correction. J Chem Phys. (1992);96(3):2155–2160.
  24. Nuha, D., Evren, A. E., Yılmaz Cankılıç, M., Yurttaş, L. Design and synthesis of novel 2,4,5-thiazole derivatives as 6-APA mimics and antimicrobial activity evaluation. Phosphorus Sulfur Silicon Relat Elem. (2021);196(10):954–960.
  25. Turkoglu G, Berber H. Novel formazan derivatives containing phenylsulfanyl and carbonyl units: synthesis, optical and electrochemical properties. RSC Adv. (2016);6(98):96065–96078.
  26. Fahim AM, Shalaby MA. Synthesis, biological evaluation, molecular docking and DFT calculations of novel benzenesulfonamide derivatives. J Mol Struct. (2019);1176:408–421.
  27. Hou, X., Ge, Z., Wang, T., Guo, W., Wu, J., Cui, J., Li, R. Synthesis and structure–activity relationships of a novel class of dithiocarbamic acid esters as anticancer agent. Arch Pharm (Weinheim). (2011);344(5):320–332.
  28. Parte MK, et al. Synthesis, spectral, FMOs and NLO properties based on DFT calculations of dioxidomolybdenum(VI) complex. J Coord Chem. (2021);74(4–6):584–597.
  29. Choudhary, V., Bhatt, A., Dash, D., Sharma, N. DFT calculations on molecular structures, HOMO–LUMO study, reactivity descriptors and spectral analyses of newly synthesized diorganotin(IV) 2-chloridophenylacetohydroxamate complexes. J Comput Chem. (2019);40(27):2354–2363.
  30. Fukui K. Role of frontier orbitals in chemical reactions. Science. (1982);218:747–754.
  31. Srimathi U, Nagarajan V, Chandiramouli R. Investigation on graphdiyne nanosheet in adsorption of sorafenib and regorafenib drugs: a DFT approach. J Mol Liq. (2019);277:776–785.
  32. Schwalbe, S., Hahn, T., Liebing, S., Trepte, K., Kortus, J. Fermi–Lowdin orbital self-interaction corrected density functional theory: ionization potentials and enthalpies of formation. J Comput Chem. (2018);39(29):2463–2471.
  33. Parr RG, et al. Electronegativity: the density functional viewpoint. J Chem Phys. (1978);68(8):3801–3807.
  34. Anderson Coser Gaudio AK, Takahata Y. quantitative structure–activity relationships for 1,4-dihydropyridine calcium channel antagonists (nifedipine analogues): a quantum chemical–classical approach. J Pharm Sci. (1994);83:1110–1115.
  35. Nasiri SK, Reisi-Vanani A, Hamadanian M. molecular structure, spectroscopic, local and global reactivity descriptors and NBO analysis of C₃₂H₁₂: a new buckybowl and sub-fullerene structure. Polycycl Aromat Compd. (2018);40(3):693–704.
  36. Sarkar U, Khatua M, Chattaraj PK. A tug-of-war between electronic excitation and confinement in a dynamical context. Phys Chem Chem Phys. (2012);14(5):1716–1727.
  37. Padmanabhan J, Parthasarathi R, Elango M, Subramanian V, Krishnamoorthy BS, Gutierrez-Oliva S, Toro-Labbé A, Roy DR, Chattaraj PK. multiphilic descriptor for chemical reactivity and selectivity. J Phys Chem A. (2007);111:9130–9138.
  38. Kleinman DA. Nonlinear dielectric polarization in optical media. Phys Rev. (1962);126(6):1977–1979.
  39. Hernández-Paredes, J., Glossman-Mitnik, D., Duarte-Moller, A., Flores-Holguín, N. Theoretical calculations of molecular dipole moment, polarizability, and first hyperpolarizability of glycine–sodium nitrate. J Mol Struct THEOCHEM. (2009);905(1–3):76–80.
  40. Guijarro MV. Osteosarcoma: mouse models, cell of origin and cancer stem cell. Postdoc J. (2014);2:19–30.
  41. Ertural C, Steinberg S, Dronskowski R. Development of a robust tool to extract Mulliken and Lowdin charges from plane waves and its application to solid-state materials. RSC Adv. (2019);9(51):29821–29830.
  42. Asghar, S., Mushtaq, N., Ahmed, A., Anwar, L., Munawar, R., Akhtar, S. Potential of tryptamine derivatives as multi-target directed ligands for alzheimer’s disease: AChE, MAO-B, and COX-2 as molecular targets. Molecules. (2024);29(2).
  43. Wu, J., Zhang, H., Wang, Y., Yin, G., Li, Q., Zhuo, L., Wang, Z. From tryptamine to the discovery of efficient multi-target directed ligands against cholinesterase-associated neurodegenerative disorders. Front Pharmacol. (2022);13:1036030.
  44. Nuha, D., Evren, A. E., Özkan, B. N. S., Gundogdu‐Karaburun, N., Karaburun, A. Ç. Design, synthesis, biological evaluation, and molecular modeling simulations of new phthalazine-1,4-dione derivatives as anti-alzheimer’s agents. Arch Pharm (Weinheim). (2024);357(10):e2400067.
  45. Evren, A. E., Nuha, D., Özkan, B. N., Kahraman, Ç., Gönülalan, E. M., Yurttaş, L. Design and synthesis of phenoxymethyl-oxadiazole compounds against alzheimer’s disease. Arch Pharm (Weinheim). (2024);357(8):e2400115.
  46. Politzer P, Murray JS. the fundamental nature and role of the electrostatic potential in atoms and molecules. Theor Chem Acc. (2002);108(3):134–142.
  47. Arif, R., Rana, M., Yasmeen, S., Khan, M. S., Abid, M., Khan, M. S. facile synthesis of chalcone derivatives as antibacterial agents: synthesis, DNA binding, molecular docking, DFT and antioxidant studies. J Mol Struct. (2020);1208.
  48. Evren, A. E., Nuha, D., Dawbaa, S., Sağlık, B. N., Yurttaş, L. Synthesis of novel thiazolyl hydrazone derivatives as potent dual monoamine oxidase–aromatase inhibitors. Eur J Med Chem. (2022);229:114097.
  49. Isyaku Y, Uzairu A, Uba S. computational studies of a series of 2-substituted phenyl-2-oxo-, 2-hydroxy- and 2-acyloxyethylsulfonamides as potent antifungal agents. Heliyon. (2020);6(4):e03724.
  50. Evren, A. E., Dawbaa, S., Yavuz, Ş. A., Gül, Ü. D., Yurttaş, L. design and synthesis of new 4-methylthiazole derivatives: in vitro and in silico studies of antimicrobial activity. J Mol Struct. (2021);1241.