Molecular Docking and ADME Studies for (E)-2,4-di-tert butyl-6-((4-fluorophenylimino)methyl) phenol ve (E)-2,4-di-tert-butyl-6-((3-iodo-4-methylphenylimino)methyl) phenol Compounds

Yıl 2023, , 997 - 1011, 15.09.2023

Enis Güzel , Mustafa Macit , Metin Yavuz

https://doi.org/10.31466/kfbd.1283044

Öz

Molecular Docking study was performed with Cannabinoid Receptor 1 (CNR1) protein structure, which is the target protein structure of the ((E)-2,4-di-tert butyl-6-((4-fluorophenyl imino)methyl)phenol (I) and (E)-2,4-di-tert-butyl-6-((3-iodo-4-methylphenylimino)methyl)phenol (II) Schiff-based compounds mentioned in the title. The effects of covalent and non-covalent ionic bonds, hydrogen bonds, and Van der Waals bonds on the 3-dimensional (3D) folding of the protein structure are discussed after the ligand structures and the target protein structure are combined. Also, the hydrophobic effects of compound-protein interaction are discussed. In addition, physicochemical properties, lipophilicity, pharmacokinetic properties, liquid solubility, medicinal chemistry and drug similarity studies of these two drug candidate compounds were theoretically investigated. As a result of the theoretical calculations, when the compound (I) and compound (II) of CNR 1 protein structure with the H interaction was examined, it was concluded that the donor-acceptor interaction of the protein structure of compound (I), which has an iodine atom attached to the aromatic benzene ring, was higher than that of compound (II), which has fluorine attached to the benzene ring. When the target protein structure of compound (I) and compound (II) with the intermolecular polar charge states are examined, it is thought to be neutral and stable against the new molecule to be added from outside.

Anahtar Kelimeler

Addiction, ADME, Schiff Base, Molecular Docking

(E)-2,4-di-tert bütil-6-((4-florofenilimino)metil)fenol ve (E)-2,4-di-tert-bütil-6-((3-iyodo-4-metilfenilimino)metil)fenol Bileşikleri için Moleküler Docking ve ADME Çalışmaları

Öz

Başlıkta belirtilen ((E)-2,4-di-tert bütil-6-((4-florofenilimino)metil)fenol (I) ve (E)-2,4-di-tert-bütil-6-((3-iyodo-4-metilfenilimino)metil)fenol (II) Schiff bazlı bileşiklerin hedef protein yapısı olan Kannabinoid Reseptörü 1 (CNR 1) protein yapısı ile Moleküler Docking çalışması yapılmıştır. Ligand yapıları ile hedef protein yapısı birleştirildikten sonra oluşan kovalent bağlar ve kovalent olmayan iyonik bağlar, hidrojen bağları, Van der Waals bağlarının protein yapısının 3-boyutlu (3B) katlanması üzerindeki etkisi tartışılmıştır. Bunlara ek olarak, ilaç adayı bu iki bileşiğin fizikokimyasal özellikleri, lipofilisitesi, farmokinetik özellikleri, sıvı çözünürlükleri, tıbbi kimya ve ilaç benzerliği araştırmaları kuramsal olarak yapılmıştır. Yapılan kuramsal hesaplamalar sonucunda bileşik (I) ve bileşik (II)’nin CNR 1 protein yapısı ile H etkileşimi incelendiğinde aromatik benzen halkasına iyot atomu bağlı olan bileşik (I) protein yapısı alıcı (donör) verici (akseptör) etkileşiminin, benzen halkasına flor bağlı olan bileşik (II)’ye göre daha fazla olduğu sonucuna ulaşılmıştır. Bileşik (I) ve bileşik (II)’nin hedef protein yapısı ile moleküller arası kutuplu yük durumları incelendiğinde, dışarıdan eklenecek yeni moleküle karşı nötr ve kararlı olduğu düşünülmektedir.

Anahtar Kelimeler

Bağımlılık, ADME, Schiff Bazı, Moleküler Docking

Kaynakça

• Abd-Elzaher, M. M., Labib, A. A., Mousa, H. A., Moustafa, S. A., Ali, M. M., and El-Rashedy, A. A. (2016). Synthesis, anticancer activity and molecular docking study of Schiff base complexes containing thiazole moiety. Beni-suef university journal of basic and applied sciences, 5(1), 85-96.
• Aboul-Fadl, T., Mohammed, F. A. H., and Hassan, E. A. S. (2003). Synthesis, antitubercular activity and pharmacokinetic studies of some Schiff bases derived from 1-alkylisatin and isonicotinic acid hydrazide (INH). Archives of pharmacal research, 26, 778-784.
• Allan, G. M., Finley, C. R., Ton, J., Perry, D., Ramji, J., Crawford, K., ... and Kolber, M. R. (2018). Systematic review of systematic reviews for medical cannabinoids: Pain, nausea and vomiting, spasticity, and harms. Canadian Family Physician, 64(2), e78-e94.
• Bijo, M., Vakketh, S. S., and Kumar, S. S. (2010). Synthesis, molecular properties and anthelmintic activity of some Schiff bases of 1, 3, 4 thiadiazole derivatives. Der pharma chemica, 2(5), 337-343.
• Bingöl Alpaslan, Y., Sert, Y., Sohtun, W. P., Velusamy, M., and Gökce, H. (2021). Structural, spectral, electronic, and molecular docking investigations on N, N‐dimethyl‐2‐[(1E)‐({[(methylsulfanyl) methanethioyl] amino} imino) methyl] aniline. Journal of the Chinese Chemical Society, 68(6), 971-988.
• Çetinkaya, E. A., Koç, A., Koç, H. K., Karabıyık, H., Karabıyık, H., Üstün, E., and Özdemir, İ. (2023). Synthesis, Characterization and Antimicrobial Properties of Silver Complexes Derived from 5, 6-Dimethylbenzimidazol-2-ylidene. Polyhedron, 116383.
• Daina, A., Michielin, O., and 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.
• Daina, A., Michielin, O., and Zoete, V. (2019). SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic acids research, 47(W1), W357-W364.
• DeLano, W. L. (2002). Pymol: An open-source molecular graphics tool. CCP4 Newsl. Protein Crystallogr, 40(1), 82-92.
• Dhar, D. N., and Taploo, C. L. (1982). Schiff-bases and their applications. Journal of Scientific & Industrial Research, 41(8), 501-506.
• Dominiak, P. M., Grech, E., Barr, G., Teat, S., Mallinson, P., and Woźniak, K. (2003). Neutral and ionic hydrogen bonding in Schiff bases. Chemistry–A European Journal, 9(4), 963-970
• Elemike, E. E., Onwudiwe, D. C., Nwankwo, H. U., and Hosten, E. C. (2017). Synthesis, crystal structure, electrochemical and anti-corrosion studies of Schiff base derived from o-toluidine and o-chlorobenzaldehyde. Journal of Molecular Structure, 1136, 253-262.
• Elphick, M. R., and Egertova, M. (2001). The neurobiology and evolution of cannabinoid signalling. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 356(1407), 381-408.
• Emirik, M., Karaoğlu, K., Serbest, K., Çoruh, U., and Lopez, E. M. V. (2015). Two novel unsymmetrical ferrocene based azines and their complexing abilities towards Cu (II): Spectroscopy, crystal structure, electrochemistry and DFT calculations. Polyhedron, 88, 182-189.
• Ergüzeloğlu, E. (2019). C21H26FNO, C32H46N2O2 ve C22H28INO bileşiklerinin X-ışınları ve bazı spektroskopik yöntemlerle özelliklerinin incelenmesi Yüksek Lisans Tezi Ondokuz Mayıs Üniversitesi, Fen Bilimleri Enstitüsü, Samsun .
• Güzel, E., Demircioğlu, Z., Çiçek, C., Ağar, E., and Yavuz, M. (2021). Experimental (XRD, FTIR, UV–Vis, NMR) and theoretical investigations (chemical activity descriptors, NBO, DNA/ECT) of (E)-2-((2-hydroxy-5-methoxybenzylidene) amino)-4-nitrophenol. Molecular Crystals and Liquid Crystals, 724(1), 58-76.
• Hoon, M., Okawa, H., Della Santina, L., and Wong, R. O. (2014). Functional architecture of the retina: development and disease. Progress in retinal and eye research, 42, 44-84.
• Hua, T., Vemuri, K., Pu, M., Qu, L., Han, G. W., Wu, Y., ... and Liu, Z. J. (2016). Crystal structure of the human cannabinoid receptor CB1. Cell, 167(3), 750-762.
• Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., ... and Hassabis, D. (2021). Highly accurate protein structure prediction with AlphaFold. Nature, 596(7873), 583-589.
• Kajal, A., Bala, S., Kamboj, S., Sharma, N., and Saini, V. (2013). Schiff bases: a versatile pharmacophore. Journal of Catalysts.
• Kalecik, S., Güzel, E., Doğan, O. E., Ağar, E., ve Yavuz, M. (2022). (E)-4-bromo-5-floro-2-(((4-(fenilamino) fenil) imino) metil) fenol Bileşiğinin Kimyasal Aktivite ve Spektroskopik Çalışmaları. Karadeniz Fen Bilimleri Dergisi, 12(2), 821-840.
• Li, Y., Guo, C., Yang, J., Wei, J., Xu, J., and Cheng, S. (2006). Evaluation of antioxidant properties of pomegranate peel extract in comparison with pomegranate pulp extract. Food chemistry, 96(2), 254-260.
• 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, 1; 46 (1-3): 3-26.
• Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S. and Olson, A. J. (2009). Autodock4 and AutoDockTools4: automated docking with selective receptor flexiblity. J. Computational Chemistry, 16: 2785-91.
• Pagotto, U., Marsicano, G., Cota, D., Lutz, B., and Pasquali, R. (2006). The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocrine reviews, 27(1), 73-100.
• Pertwee, R. G. (2006). The pharmacology of cannabinoid receptors and their ligands: an overview. International journal of obesity, 30(1), S13-S18.
• Porcella, A., Maxia, C., Gessa, G. L., and Pani, L. (2000). The human eye expresses high levels of CB1 cannabinoid receptor mRNA and protein. European Journal of Neuroscience, 12(3), 1123-1127.
• Şahin, Z. S., Şenöz, H., Tezcan, H., and Büyükgüngör, O. (2015). Synthesis, spectral analysis, structural elucidation and quantum chemical studies of (E)-methyl-4-[(2-phenylhydrazono) methyl] benzoate. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 143, 91-100.
• Sathe, B. S., Jayachandran, E., Jagtap, V. A., and Sreenivasa, G. M. (2011). Anthelmintic activity of newly synthesized moieties of fluoro benzothiazole Schiff’s bases. Research Journal of Pharmaceutical, Biological and Chemical Sciences, 2(1), 510-515.
• Seth, A., Sharma, P. A., Tripathi, A., Choubey, P. K., Srivastava, P., Tripathi, P. N., and Shrivastava, S. K. (2018). Design, synthesis, evaluation and molecular modeling studies of some novel N-substituted piperidine-3-carboxylic acid derivatives as potential anticonvulsants. Medicinal Chemistry Research, 27, 1206-1225.
• Shao, Z., Yin, J., Chapman, K., Grzemska, M., Clark, L., Wang, J., and Rosenbaum, D. M. (2016). High-resolution crystal structure of the human CB1 cannabinoid receptor. Nature, 540(7634), 602-606.
• Süleymanoğlu, N., Ustabaş, R., Direkel, Ş., Alpaslan, Y. B., and Ünver, Y. (2017). 1, 2, 4-triazole derivative with Schiff base; thiol-thione tautomerism, DFT study and antileishmanial activity. Journal of Molecular Structure, 1150, 82-87.
• Tarı, G. Ö., and Ağar, E. (2017). Synthesis, crystal structure, spectroscopic characterization and theoretical calculations of (Z)-N-(naphthalen-2-yl)-1-(5-nitrothiophen-2-yl) methanimine. Journal of Molecular Structure, 1147, 56-68.
• Temel, E., Alaşalvar, C., Eserci, H., and Ağar, E. (2017). Experimental (X-ray, IR and UV–vis.) and DFT studies on cocrystallization of two tautomers of a novel Schiff base compound. Journal of Molecular Structure, 1128, 5-12.
• Varadi, M., Anyango, S., Deshpande, M., Nair, S., Natassia, C., Yordanova, G., ... and Velankar, S. (2022). AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic acids research, 50(D1), D439-D444.
• Vashi, K., and Naik, H. B. (2004). Synthesis of novel Schiff base and azetidinone derivatives and their antibacterial activity. E-Journal of Chemistry, 1(5), 272-275.
• Venkatesh, P., and Tiwari, V. S. (2016). Design and synthesis of Quinazolinone, Benzothiazole derivatives bearing guanidinopropanoic acid moiety and their Schiff bases as cytotoxic and antimicrobial agents. Arabian Journal of Chemistry, 9, S914-S925.