SAR Analysis and Molecular Modeling Study of Some Pyridazine Derivatives for Discovery of New CDK2 Inhibitors

Abstract

Pyridazines, which are rarely found in nature and are among the building blocks of macromolecules that are essential for the life of most living things, are a family of heterocyclic compounds with many different biological activities. In this study, it was aimed to examine the potential of 8 different pyridazine derivative compounds synthesized by Ünal et al. to be cyclin-dependent kinase 2 (CDK2) inhibitors, which take role in important cellular processes such as DNA replication so that the abnormalities observed in their activities are determined to be associated with cancer pathology. For this purpose, the conformer searchs of the compounds were performed using the semi-experimental PM6 method on the SPARTAN'14 program, the geometry optimizations and Structure-Activity Relations (SAR) analyzes were performed using the HF/6-31G(d) method. Furthermore, molecular docking studies of each compound for the selected active sites for the purpose of the study was carried out using Autodock Tools-1.5.6 and Autodock Vina programs. As a result of the study; it was determined that 1a2b (-10.8 kcal.mol-1) and 1b2b (-10.5 kcal.mol-1) compounds, which have the best affinity values among the compounds examined, have a high potential to be CDK2 inhibitors and it was become clear that advanced studies should be carried out considering the prominent features of these compounds for the design of new anticancer ligands.

Keywords

• Pyridazine
• Molecular docking
• CDK2
• Anticancer
• Pyridazine, Molecular docking, CDK2, Anticancer

Yeni CDK2 İnhibitörlerinin Keşfedilmesi İçin Bazı Piridazin Türevi Bileşiklerin SAR Analizi ve Kenetlenme Çalışması

Abstract

Doğada nadir olarak bulunan ve çoğu canlının yaşamı için elzem olan makro moleküllerin yapı taşları arasında yer alan piridazinler pek çok farklı biyolojik aktiviteye sahip olan bir heterosiklik bileşik ailesidir. Bu çalışmada Ünal ve grubu tarafından sentezlenen yeni 8 farklı piridazin türevi bileşiğin DNA replikasyonu gibi önemli hücresel süreçlerde rol alan ve bu nedenle aktivitesinde gözlenen anormalliklerin kanser patolojisi ile ilişkili olduğu belirlenen siklin bağımlı kinaz 2 (CDK2) inhibitörü olabilme potansiyellerinin incelenmesi amaçlanmıştır. Bu amaç doğrultusunda bileşiklerin konformer taramaları SPARTAN’14 programı üzerinde yarı deneysel PM6 yöntemi ile, geometri optimizasyonları ve Yapı-Aktivite İlişkileri (SAR) analizleri ise HF/6-31G(d) yöntemi kullanılarak gerçekleştirilmiştir. Her bir bileşiğin çalışmanın amacı doğrultusunda seçilen aktif bölgelere moleküler kenetlenme işlemleri ise Autodock Tools-1.5.6 ve Autodock Vina programları kullanılarak gerçekleştirilmiştir. Bu çalışma sonucunda; incelenen bileşikler arasından en iyi afinite değerlerine sahip olan 1a2b (-10,8 kkal.mol-1) ve 1b2b (-10,5 kkal.mol-1) bileşiklerinin CDK2 inhibitörü olabilme potansiyellerinin yüksek olduğu belirlenmiş ve yeni antikanser ajanı ligandların tasarımında bu bileşiklerin öne çıkan özelliklerinin dikkate alınmasıyla birlikte ilgili ileri düzey çalışmaların yapılması gerektiği açığa çıkmıştır.

Keywords

• Piridazin
• Moleküler kenetlenme
• CDK2
• Antikanser

References

1. [1] Menteşe, E., Yılmaz, F., Emirik, M., Ülker, S., Kahveci, B. 2018. Synthesis, molecular docking and biological evaluation of some benzimidazole derivatives as potent pancreatic lipase inhibitors. Bioorganic Chemistry, 76, 478–486.
2. [2] Alaşalvar, C., Soylu, M. S., Ünver, H., Ocak Iskeleli, N., Yildiz, M., Çiftçi, M., Banoǧlu, E. 2014. Crystal structure and DFT calculations of 5-(4-Chlorophenyl)-1-(6- methoxypyridazin-3-yl)-1H-pyrazole-3-carboxylic acid. Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 132, 555–562.
3. [3] Arun, A. K., Mohan, K., Riyaz, S. 2013. Structure guided inhibitor designing of CDK2 and discovery of potential leads against cancer. Journal of Molecular Modeling, 19(9), 3581–3589.
4. [4] Otyepka, M., Kryštof, V., Havlíček, L., Siglerová, V., Strnad, M., Koča, J. 2000. Docking-based development of purine-like inhibitors of cyclin-dependent kinase-2. Journal of Medicinal Chemistry, 43(13), 2506–2513.
5. [5] Kumar, A., Zhang, K. Y. J. 2016. A pose prediction approach based on ligand 3D shape similarity. Journal of Computer-Aided Molecular Design, 30(6), 457–469.
6. [6] Baby, B., Antony, P., Al Halabi, W., Al Homedi, Z., Vijayan, R. 2016. Structural insights into the polypharmacological activity of quercetin on serine/threonine kinases. Drug Design, Development and Therapy, 10, 3109–3123.
7. [7] Babu, P. A., Narasu, M. L., Srinivas, K. 2007. Pyridines, pyridazines and guanines as CDK2 inhibitors: A review. Arkivoc, 2007(2), 247–265.
8. [8] Davies, T. G., Tunnah, P., Meijer, L., Marko, D., Eisenbrand, G., Endicott, J. A., Noblel, M. E. M. 2001. Inhibitor binding to active and inactive CDK2: The crystal structure of CDK2-cyclin A/indirubin-5-sulphonate. Structure, 9(5), 389–397.

9. [9] Prabavathi, N., Senthil Nayaki, N., Venkatram Reddy, B. 2015. Molecular structure, vibrational spectra, natural bond orbital and thermodynamic analysis of 3,6-dichloro-4-methylpyridazine and 3,6-dichloropyridazine-4-carboxylic acid by dft approach. Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 136, 1134–1148.
10. [10] Qin, X. F., Wang, F., Wu, H. S. 2014. Density functional studies of the stepwise substitution of pyridine, pyridazine, pyrimidine, pyrazine, and 1,3,5-triazine with BCO. Journal of Molecular Modeling, 20(1), 2079-2085.
11. [11] Breda, S., Reva, I. D., Lapinski, L., Nowak, M. J., Fausto, R. 2006. Infrared spectra of pyrazine, pyrimidine and pyridazine in solid argon. Journal of Molecular Structure, 786, 193–206.
12. [12] Reimers, J. R., Cai, Z.-L. 2012. Hydrogen bonding and reactivity of water to azines in their S1 (n,π*) electronic excited states in the gas phase and in solution. Physical Chemistry Chemical Physics, 14(25), 8791.
13. [13] George, R. F., Saleh, D. O. 2016. Synthesis, vasorelaxant activity and 2D-QSAR study of some novel pyridazine derivatives. European Journal of Medicinal Chemistry, 108, 663–673.
14. [14] Soliman, S. M., Albering, J., Abu-Youssef, M. A. M. 2015. Molecular structure, spectroscopic properties, NLO, HOMO-LUMO and NBO analyses of 6-hydroxy-3(2H)-pyridazinone. Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 136, 1086–1098.
15. [15] Ünal, D., Saripinar, E., Akçamur, Y. 2006. A new method for the preparation of pyridazine systems: Experimental data and semiempirical PM3 calculations. Turkish Journal of Chemistry, 30(6), 691–701.
16. [16] Spartan 14v1.1.4 (2014) Wavefunction, Inc., Irvine, CA. (https://www.wavefun.com/)
17. [17] Stewart, J. J. P. 2007. Optimization of parameters for semiempirical methods V: Modification of NDDO approximations and application to 70 elements. Journal of Molecular Modeling, 13(12), 1173–1213.
18. [18] Stewart, J. J. P. 2008. Application of the PM6 method to modeling the solid state. Journal of Molecular Modeling, 14(6), 499–535.
19. [19] McWeeny, R., Diercksen, G. 1968. Self-consistent perturbation theory. II. Extension to open shells. The Journal of Chemical Physics, 49(11), 4852–4856.
20. [20] Pople, J. A., Nesbet, R. K. 1954. Self-consistent orbitals for radicals. The Journal of Chemical Physics, 22(3), 571–572.
21. [21] Roothaan, C. C. J. 1951. New developments in molecular orbital theory. Reviews of Modern Physics, 23(2), 69–89.
22. [22] Dassault Systèmes BIOVIA, Discovery Studio Visualizer, V2. San Diego: Dassault Systèmes. 2017.
23. [23] Sanner, M. F. 1999. Python: a programming language for software integration and development. Journal of Molecular Graphics & Modelling, 17(1), 57–61. [24] Trott, O., Olson, A. 2010. AutoDock Vina: inproving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. Journal of Computational Chemistry, 31(2), 455–461.