DFT Calculations, ADME Analysis and Molecular Docking Studies of the Compound AHTPO With the Digestive Enzyme Trypsin Found in Cold-Adapted Fish Species

Year 2025, Volume: 29 Issue: 4, 383 - 401, 31.08.2025

Erdi Anıl Tanrıverdi , Aslıhan Aycan Tanrıverdi , Ümit Yıldıko

https://doi.org/10.16984/saufenbilder.1646947

Abstract

For the special amine 7-Amino-3-(4-aminophenyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (AHTPO), previously reported experimental biological activities served as the foundation for further studies. Computational chemistry and molecular simulation techniques were subsequently applied to investigate AHTPO. Its interactions with trypsin enzymes derived from cold-adapted fish species were examined. The compound's biological activity and pharmacokinetic properties were assessed using DFT calculations, molecular docking, and ADME analyses. Molecular docking results indicated that AHTPO exhibits strong binding affinities with the 1A0J and 2TBS enzymes, with the binding to 2TBS being energetically more favorable. Additionally, ADME analysis revealed that while the AHTPO shows potential for pharmaceutical applications, its gastrointestinal absorption and blood-brain barrier permeability may present certain limitations. Regarding its electronic and optical properties, AHTPO's high dipole moment and polarizability values enhance its flexibility and adaptability in biological environments. The HOMO-LUMO energy gap suggests that the AHTPO achieves a balance between stability and reactivity, enabling high activity in biomolecular interactions. These findings highlight the promising pharmacological potential of AHTPO in binding with trypsin enzymes, suggesting its viability as a therapeutic agent.

Keywords

Thiazolo , Pyrimidine , DFT , Molecular docking , Trypsin

References

• D. Cai, Z. H. Zhang, Y. Chen, X. J. Yan, S. T. Zhang, L. J. Zou, L. H. Meng, F. Li, B. J. Fu, “Synthesis of some new thiazolo[3,2a]pyrimidine derivatives and screening of their in vitro antibacterial and antitubercular activities,” Medicinal Chemistry Research, vol. 25, pp. 292-302, 2016.
• J. C. Roach, "A clade of trypsins found in cold-adapted fish," Proteins: Structure, Function, and Bioinformatics, vol. 47, pp. 31-44, 2002.
• A. Muhlia-Almazán, A. Sánchez-Paz, F. L. García-Carreño, “Invertebrate trypsins: A review,” J Comp Physiol B, vol. 178, pp. 655-72, 2008.
• R. T. Azuma, “Survey of augmented reality,” Presence: Teleoperators and Virtual Environments, vol. 6, no. 4, pp. 355-385, 1997.
• O. Gon, P. C. Heemstra, “Fishes of the southern ocean,” Reviews in Fish Biology and Fisheries, vol. 2, pp. 344-345, 1990.
• G. Bianchi, “Sustainable fisheries within an LME context,” Environmental Development, vol. 17, no. 1, pp. 182-192, 2016.
• P. C. Agu, C. A. Afiukwa, O. U. Orji, E. M. Ezeh, I. H. Ofoke, C. O. Ogbu, E. I. Ugwuja, P. M. Aja, “Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in diseases management,” Scientific Reports, vol. 13, pp. 13398, 2023.
• S. Demirel, A. Güller, M. Usta, Z. Kurt, G. Korkmaz, “Coat protein of alfalfa mosaic alfamovirus (AMV) from Türkiye: Genetic inference and in silico docking analysis for potential antiphytoviral purposes. Notulae Botanicae Horti Agrobotanici Cluj-Napoca,” vol. 52, no. 1, 2024.
• U. S. T. A. Mustafa, A. Güller, S. Demirel, G. Korkmaz, K. U. R. T. Zeynelabidin, “New insights into tomato spotted wilt orthotospovirus (TSWV) infections in Türkiye: Molecular detection, phylogenetic analysis, and in silico docking study,” Notulae Botanicae Horti Agrobotanici Cluj-Napoca, vol. 51, no. 3, pp. 13245-13245, 2023.
• S. Choudhuri, M. Yendluri, S. Poddar, A. Li, K. Mallick, S. Mallik, B. Ghosh, “Recent advancements in computational drug design algorithms through machine learning and optimization,” Kinases and Phosphatases [Online], pp. 117-140, 2023.
• C. Yang, E. A. Chen, Y. Zhang, “Protein-Ligand Docking in the Machine-Learning Era,” Molecules, vol. 27, 2022.J.
• Abdullah, A. A. Tanriverdi, A. A. Khan, S. J. Lee, J. B. Park, Y. S. Kim, U. Yildiko, K. Min, M. Alam, “Selenium-substituted conjugated small molecule: Synthesis, spectroscopic, computational studies, antioxidant activity, and molecular docking,” Journal of Molecular Structure, vol. 1304, pp.137694, 2024.
• R. Tiwari, K. Mahasenan, R. Pavlovicz, C. Li, W. Tjarks, “Carborane clusters in computational drug design: A Comparative docking evaluation using AutoDock, FlexX, Glide, and Surflex," Journal of chemical information and modeling, vol. 49, pp. 1581-9, 2009.
• C. George Priya Doss, C. Chakraborty, V. Narayan, D. Thirumal Kumar, “Computational Approaches and Resources in Single Amino Acid Substitutions Analysis Toward Clinical Research,” In Advances in Protein Chemistry and Structural Biology, Donev, R., Ed. Chapter Ten -vol. 94, pp. 365-423, Academic Press: 2014.
• K. W. Lexa, H. A. Carlson, “Protein flexibility in docking and surface mapping,” Q Rev Biophys, vol. 45, pp. 301-43, 2012.
• N. K. Borah, Y. Tripathi, A. Tanwar, D. Tiwari, A. Sinha, S. Sharma, N. Jabalia, R. J. Mani, S. Santoshi, H. Bansal, “Artificial intelligence-powered molecular docking,” In Artificial Intelligence and Machine Learning in Drug Design and Development, pp. 157-188, 2024.
• H. K. Schrøder, N. P. Willassen, A. O. Smalås, “Structure of a Non-psychrophilic trypsin from a cold-adapted fish species,” Acta Crystallographica Section D, vol. 54, pp. 780-798, 1998.
• A. O. Smalås, E. S. Heimstad, A. Hordvik, N. P. Willassen, R. Male, “Cold adaption of enzymes: Structural comparison between salmon and bovine trypsins,” Proteins: Structure, Function, and Bioinformatics, vol. 20, pp. 149-166, 1994.
• S. O. Oselusi, P. Dube, A. I. Odugbemi, K. A. Akinyede, T. L. Ilori, E. Egieyeh, N. R. S. Sibuyi, M. Meyer, A. M. Madiehe, G. J. Wyckoff, S. A. Egieyeh, “The role and potential of computer-aided drug discovery strategies in the discovery of novel antimicrobials,” Computers in Biology and Medicine, vol. 169, p. 107927, 2024.
• S. Racioppi, P. Lolur, P. Hyldgaard, M. Rahm, “A density functional theory for the average electron energy,” Journal of Chemical Theory and Computation, vol. 19, pp. 799-807, 2023.
• K. Gören, M. Bağlan, Ü. Yıldıko, “Analysis by DFT, adme and docking studies of N'-(4-Hydroxy-3-Methoxybenzylidene) Naphtho [2, 3-B] Furan-2-Carbohydrazide,” ESTU Science, vol. 13, no. 1, pp. 7-23, 2025.
• A. J. Cohen, P. Mori-Sánchez, W. Yang, “Challenges for Density Functional Theory,” Chemical Reviews, vol. 112, pp. 289-320, 2012.
• U. Yildiko, A. A. Tanriverdi, “A novel sulfonated aromatic polyimide synthesis and characterization: Energy calculations, QTAIM simulation study of the hydrated structure of one unit,” Bulletin of the Korean Chemical Society, vol. 43, pp. 822-835, 2022.
• M. Bursch, J. M. Mewes, A. Hansen, S. Grimme, “Best-Practice DFT Protocols for Basic Molecular Computational Chemistry,” Angewandte Chemie International Edition, vol. 61, p. e202205735, 2022.
• K. Gören, Ü. Yıldıko, “Aldose reductase evaluation against diabetic complications using ADME and molecular docking studies and DFT calculations of spiroindoline derivative molecule,” Süleyman Demirel University Journal of Natural and Applied Sciences, vol. 28, pp. 281-292, 2024.
• C. D. Gandhi, P. Sappidi, “Molecular Dynamics Simulation Study on the Structural and Thermodynamic Analysis of Oxidized and Unoxidized Forms of Polyaniline,” The Journal of Physical Chemistry B, vol. 128, pp. 10735-10748, 2024.
• Ü. Yildiko, A. Ç. Ata, A. A. Tanriverdi, İ. Çakmak, “Investigation of novel diethanolamine dithiocarbamate agent for RAFT polymerization: DFT computational study of the oligomer molecules,” Bulletin of Materials Science, vol. 44, p. 186, 2021.
• A. I. Osman, A. Ayati, P. Krivoshapkin, B. Tanhaei, M. Farghali, P. S. Yap, A. Abdelhaleem, “Coordination-driven innovations in low-energy catalytic processes: Advancing sustainability in chemical production,” Coordination Chemistry Reviews, vol. 514, p. 215900, 2024.
• K. Gören, M. Bağlan, Ü. Yıldıko, “Antimicrobial, and Antitubercular Evaluation with ADME and Molecular Docking Studies and DFT Calculatıons of (Z)-3-((1-(5-amino-1, 3, 4-thiadiazol-2-yl)-2-Phenylethyl) imino)-5-nitroindolin-2-one Schiff Base,” The Black Sea Journal of Sciences, vol. 14, pp. 1694-1708, 2024.
• M. Frisch, F. Clemente, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino and G. Zhe, Gaussian 9.
• Schrödinger Release 2017-3: Schrödinger Suite 2017-3 Protein Preparation Wizard, Epik, Schrödinger, LLC, New York, NY, Impact, Schrödinger, LLC, New York, NY, 2017; LigPrep, Schrödinger, LLC, New York, NY, 2017; Prime, Schrödinger, LLC, New York, NY, 2017; QikProp, Schrödinger, LLC, New York, NY, 2017.
• Ü. Yildiko, F. Türkan, A. A. Tanriverdi, A. C. Ata, M. N. Atalar, İ. Cakmak, “Synthesis, enzymes inhibitory properties and characterization of 2- (bis (4-aminophenyl) methyl) butan-1-ol compound: Quantum simulations, and in-silico molecular docking studies,” Journal of the Indian Chemical Society, vol. 98, p.100206, 2021.
• SYSTÈMES BDSD, BIOVIA Corporate Europe, BIOVIA 334 Cambridge Science Park, Cambridge CB4 0WN, England, 2016.
• L. Fu, S. Shi, J. Yi, N. Wang, Y. He, Z. Wu, J. Peng, Y. Deng, W. Wang, C. Wu, A. Lyu, X. Zeng, W. Zhao, T. Hou, D. Cao, “ADMETlab 3.0: An updated comprehensive online ADMET prediction platform enhanced with broader coverage, improved performance, API functionality and decision support,” Nucleic Acids Research, vol. 52, pp. W422-W431, 2024.
• M. Quirós, S. Gražulis, S. Girdzijauskaitė, A. Merkys, A. Vaitkus, “Using SMILES strings for the description of chemical connectivity in the Crystallography Open Database,” Journal of Cheminformatics, vol. 10, p. 23, 2018.
• E. Akbas, E. Ergan, E. Sahin, S. Ekin, M. Cakir, Y. Karakus, “Synthesis, characterization, antioxidant properties and DFT calculation of some new pyrimidine derivatives,” Phosphorus, Sulfur, and Silicon and the Related Elements vol. 194, pp. 796-802, 2019.
• B. Kartal, A. A. Tanriverdi, U. Yildiko, A. T. Tekes, I. Çakmak, “Polyimide synthesis and characterizations: DFT-assisted computational studies on structural units,” Iranian Polymer Journal, 2024.
• A. Ç. Ata, Ü. Yildiko, A. A. Tanriverdi, R. Ebiri, E. Yiğit, İ. Orak, İ. Cakmak, “Two-step novel aromatic polyimide synthesis and characterization: Survey of energy calculations and diode applications,” Journal of Applied Polymer Science, vol. 140, p. e53689, 2023.
• U. Yildiko, A. A. Tanriverdi, “Synthesis and characterization of pyromellitic dianhydride based sulfonated polyimide: Survey of structure properties with DFT and QTAIM,” Journal of Polymer Research, vol. 29, p. 19, 2021.
• K. Gören, E. Çimen, V. Tahiroğlu, Ü. Yıldıko, “Moleculer docking and theoretical analysis of the (E)-5-((Z)-4-methylbenzylidene)-2-(((E)-4-methylbenzylidene) hydrazineylidene)-3-phenylthiazolidin-4-one Molecule,” Bitlis Eren Üniversitesi Fen Bilimleri Dergisi, vol. 13, pp. 659-672, 2024.
• S.R. Mannopantar, B. Maheshkumar, D. Ramesh, A. S. Lalasangi, H. H. Bendigeri, M. N. Kalasad, V. K. Kulkarni, “Effect of Ag2O nanoparticles on the excited state dipole moment of a novel BMNFC molecules through solvatochromic shift method,” Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, vol. 326, p. 125190, 2025.
• M. Włodarska, B. Mossety-Leszczak, “DFT studies of selected epoxies with mesogenic units–impact of molecular structure on electro-optical response,” International Journal of Molecular Sciences, vol. 22, p. 3424, 2021.
• N. Serin, T. Serin, B. Ünal, “The interaction of the dipole moment of the water molecule with the interface states of the cuprous oxide/cupric oxide junction,” Turkish Journal of Physics, vol. 24, no. 2, pp. 137-142, 2000.
• J. R. P. S. Souza, G. V. S. Mota, H. R. Bitencourt, S. G. Moreira, C. M. R. Remédios, “Spectroscopic characterization (FT-IR, RAMAN and UV–VIS), thermogravimetric analysis, XPD and DFT calculations of highly stable hydroxy-functionalized chalcone: (2E)-1-(4-hidroxyphenyl)-3-(4-methoxyphenil)-prop-2-en-1-one,” Journal of Molecular Structure, vol. 1295, p. 136702, 2024.
• N. Akter, S. Saha, M. A. Hossain, K. M. Uddin, A. R. Bhat, S. Ahmed, S. M. A. Kawsar, “Acylated glucopyranosides: FTIR, NMR, FMO, MEP, molecular docking, dynamics simulation, ADMET and antimicrobial activity against bacterial and fungal pathogens,” Chemical Physics Impact, vol. 9, p. 100700, 2024.
• K. Gören, M. Bağlan, Ü Yıldıko, “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, vol. 14, pp. 1186-1199, 2024.
• M. Guo, M. Ji, W. Cui, “Theoretical investigation of HER/OER/ORR catalytic activity of single atom-decorated graphyne by DFT and comparative DOS analyses,” Applied Surface Science, vol. 592, p. 153237, 2022.
• Z. A. Abdallah, A. M. Abdelfattah, A. A. M. Ahmed, “Benzo[6,7]cyclohepta[1,2-d]pyrazolo[1,5-a]pyrimidines: Regioselective synthesis of a novel ring system, DFT-based NMR prediction, local reactivity indexes, and MEP analysis,” Journal of Molecular Structure, vol. 1321, p. 140030, 2025.
• T. Pantsar, A. Poso, “Binding Affinity via Docking: Fact and Fiction,” Molecules [Online], vol. 23, p. 1899, 2018.
• D. G. Solgun, A. A. Tanriverdi, U. Yildiko, M. S. Ağirtaş, “Synthesis of axially silicon phthalocyanine substituted with bis- (3,4-dimethoxyphenethoxy) groups, DFT and molecular docking studies,” Journal of Inclusion Phenomena and Macrocyclic Chemistry, vol. 102, pp. 851-860, 2022.
• K. Basu, E. S. Brielle, I. T Arkin, “Hydrogen bond strengthens acceptor group: The curious case of the C–H···O=C Bond,” International Journal of Molecular Sciences [Online], vol. 25, p. 8606, 2024.
• C. A. Lipinski, “Lead- and drug-like compounds: The rule-of-five revolution,” Drug Discovery Today: Technologies, vol. 1, pp. 337-341, 2004.
• C. Doak Bradley, B. Over, F. Giordanetto, J Kihlberg, “Oral Druggable Space beyond the Rule of 5: Insights from drugs and clinical candidates,” Chemistry & Biology, vol. 21, pp. 1115-1142, 2014.