Oksim İçeren Bifenil Temelli İki Ligandın in silico Çalışmaları

Yıl 2021, Cilt 16, Sayı 2, 500 - 512, 25.11.2021

Güvenç GÖRGÜLÜ Bülent DEDE

https://doi.org/10.29233/sdufeffd.1011356

Öz

İki bifenil temelli ligandın moleküler kenetlenme, ADME ve toksisite özellikleri in silico olarak incelendi. Moleküler kenetlenme çalışmaları, tümör büyümesinde etkili olduğu bilinen iki faktör (VEGFR-2 ve EGFRK) kullanılarak gerçekleştirildi. İki ligand, H ve Cl olan bir atom farkı dışında yapısal açıdan benzer olarak seçildi. Bu küçük fark, ligand protein çiftlerinin moleküler kenetlenme enerji değerleri üzerinde önemli bir etki meydana getirdi. Cl atomu içeren ligand-protein kompleksleri, Cl atomunun daha yüksek elektronegatifliğinden kaynaklanabilecek büyük enerji değerlerine sahip olarak bulundu. İki konjugasyon enziminin (CYP2C19 ve CYP2C9) inhibisyonu gibi birkaç parametre dışında iki ligandın ADME özelliklerinin benzer olduğu belirlendi. Ligandların gösterdiği en büyük farkın, H içeren ligandın kanserojenliğinin ve mutajenitesinin Cl atomu içeren ligand ile ortadan kaldırması olduğu tespit edildi. İki bifenil bazlı oksim içeren ligandın ilaç benzerliği de test edildi ve tek bir atom değişiminin sonuçları, yeni ilaç tasarımı ve keşfi açısından değerlendirildi.

Anahtar Kelimeler

In silico çalışma, Moleküler kenetlenme, ADMET, İlaçbenzerlik

In Silico Studies of Two Biphenyl Based Oxime Containing Ligands

Öz

Two biphenyl based ligands were tested for their molecular docking, ADME and toxicity properties in silico. Molecular docking studies performed with two factors (VEGFR-2 and EGFRK) which are known to be effective in tumor growth. Two ligands were similar in structure except one atom difference between ligands which is H and Cl. This small difference made an important impact on the molecular docking energy scores of ligand protein couples. The Cl atom containing ligand-protein complexes showed drastically elevated energy levels which might be due to higher electronegativity of Cl atom. ADME properties of two ligands were also alike except a few parameters as the inhibition of two conjugation enzymes (CYP2C19 ve CYP2C9). The biggest difference shown by the ligands were the elimination of carcinogenicity and mutagenicity of H containing ligand by Cl atom containing ligand. Druglikeness of two biphenyl based oxime containing ligands was also tested and the results of a single atom exchange were evaluated in terms of new drug design and discovery.

Anahtar Kelimeler

: In Silico study, Molecular docking, ADMET, Druglikeness

Kaynakça

• [1] D. G. Truhlar, W. J. Howe, A. J. Hopfinger, J. Blaney, R. A. Dammkoehler, Rational Drug Design. New York: Springer, 1999.
• [2] C. Liao, M. Sitzmann, A. Pugliese, M. C. Nicklaus, “Software and resources for computational medicinal chemistry,” Future Medicinal Chemistry, 3(8), 1057-1085, 2011.
• [3] G. D. Geromichalos, C. E. Alifieris, E. G. Geromichalou, D. T. Trafalis, “Overview on the current status of virtual high-throughput screening and combinatorial chemistry approaches in multi-target anticancer drug discovery; Part I,” Journal of BUON, 21(4), 764-779, 2016.
• [4] O. Gürsoy, M. Smieško, “Searching for bioactive conformations of drug-like ligands with current force fields: how good are we?,” Journal of Cheminformatics, 9(1), 1-13, 2017.
• [5] J. Vrbanac, R. Slauter, ADME in drug discovery. In A Comprehensive Guide to Toxicology in Nonclinical Drug Development, Academic Press, 2017, pp. 39-67.
• [6] B. Chandrasekaran, S. N. Abed, O. Al-Attraqchi, K. Kuche, R. K. Tekade, Computer-aided prediction of pharmacokinetic (ADMET) properties. In Dosage form design parameters, Academic Press, 2018, pp. 731-755.
• [7] D. Premužić, A. Filarowski, M. Hołyńska, “Structure and properties of a new rigid tripodal oxime ligand,” Journal of Molecular Structure, 1136, 100-106, 2017.
• [8] Ashani Y., Silman I. 2010. Hydroxylamines and oximes: Biological properties and potential uses as therapeutic agents, John Wiley & Sons, Ltd.
• [9] N. Ferrara, H. P. Gerber, J. LeCouter, “The biology of VEGF and its receptors,” Nature Medicine, 9(6), 669-676, 2003.
• [10] D. W. Fry, A. J. Bridges, W. A. Denny, A. Doherty, K. D. Greis, J. L. Hicks, K. E. Hook, P. R. Keller, W. R. Leopold, J. A. Loo, D. J. McNamara, J. M. Nelson, V. Sherwood, J. B. Smaill, S. Trumpp-Kallmeyer, E. M. Dobrusin, “Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor,” Proceedings of the National Academy of Sciences of the USA, 95(20), 12022-12027, 1998.
• [11] I. Karataş, H. I. Uçan, “The synthesis of biphenylglyoxime and bis (phenylglyoxime) and their complexes with Cu(II), Ni(II) and Co(II),” Synthesis and Reactivity in Inorganic and Metal-Organic Chemistry, 28(3), 383-391, 1998.
• [12] N. Levin, W. H. Hartung, “Amino alcohols. XI.1 Arylglyoxylohydroxamyl chlorides2,” The Journal of Organic Chemistry, 7(5), 408-415, 1942.
• [13] D. S. Breslow, K. Brack, H. Boardman, “A one‐component sealant based on 1, 3‐dipoles,” Journal of Applied Polymer Science, 32(4), 4657-4661, 1986.
• [14] A. Grosdidier, Z. Vincent, M. Olivier, “Swissdock, A protein-small molecule docking web service based on EADock DSS,” Nucleic Acids Research, 39(2), 270-277, 2011.
• [15] E. F. Pettersen, T. D. Goddard, C. C. Huang, G. S. Couch, D. M. Greenblatt, E. C. Meng, T. E. Ferrin, “UCSF Chimera-a visualization system for exploratory research and analysis,” Journal of Computational Chemistry, 25(13), 1605-1612, 2004.
• [16] GaussView, Revision 5.0.9, R. Dennington, T. A. Keith, J. M. Millam, Semichem Inc., Shawnee Mission, KS, 2009.
• [17] A. Daina, O. Michielin, V. Zoete, “SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules,” Scientific Reports, 7(1), 1-13, 2017.
• [18] P. Banerjee, A. O. Eckert, A. K. Schrey, R. Preissner, “ProTox-II: a webserver for the prediction of toxicity of chemicals,” Nucleic Acids Research, 46(W1), W257-W263, 2018.
• [19] W. L. Chiou, “The rate and extent of oral bioavailability versus the rate and extent of oral absorption: clarification and recommendation of terminology,” Journal of Pharmacokinetics and Pharmacodynamics, 28(1), 3-6, 2001.
• [20] Y. H. Zhao, M. H. Abraham, J. Le, A. Hersey, C. N. Luscombe, G. Beck, B. Sherborne, I. Cooper, "Rate-limited steps of human oral absorption and QSAR studies," Pharmaceutical Research, 19(10), 1446-1457, 2002.
• [21] F. Montanari, G. F. Ecker, “Prediction of drug-ABC-transporter interaction-Recent advances and future challenges,” Advanced Drug Delivery Reviews, 86, 17-26, 2015.