Keywords
CDK-2
anticancer
molecular docking
molecular dynamics
How to Cite
Abstract
In the present study, around sixty-two novel coumarin derivatives were designed as CDK-2 inhibitors based on essential pharmacophoric requirements. All the designed compounds were subjected to docking study using AutoDock 4.2 against CDK-2 protein (PDB ID: 1HCK). Molinspiration and Osiris property explorer were used to predict Lipinski’s rule of five and toxicity profile. The Structure Activity Relationship study revealed that, the substitution at R1 and R4 of coumarin nucleus enhances the binding energy and inhibitory constant values from nanomolar to picomolar range. Among the designed analogues, compound 15, 28, 43 and 59 showed significant binding energy and inhibitory constant values as compared to the standard drug Olomoucine and Deschloroflavopiridol. Most of the designed analogues showed similar binding mode and orientation inside the active site of the protein as that of the standard drug, which strongly indicates that the designed molecules may emerge as potent inhibitors of CDK-2. Next, molecular dynamics study of the significantly active molecule 15 was studied for 10 ns, in order to determine the stability of the coumarin molecules inside the binding cavity of the protein. In-silico investigations suggest that the de novo designed coumarin derivatives were potentially in-silico bioactive and need to be synthesized and tested further.References
Sliwoski, G.; Kothiwale, S.; Meiler, J.; Lowe, E. W. Computational Methods in Drug Discovery. Pharmacol Rev 2013, 66 (1), 334.
https://doi.org/10.1124/pr.112.007336
Meier, P.; Finch, A.; Evan, G. Apoptosis in development. Nature 2000, 407 (6805), 796-801.
https://doi.org/10.1038/35037734
Hanks, S. K.; Quinn, A. M.; Hunter, T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 1988, 241 (4861), 42-52.
https://doi.org/10.1126/science.3291115
Schultz, J.; Ferguson, B.; Sprague Jr, G. F. Signal transduction and growth control in yeast. Curr Opin Genet Dev 1995, 5 (1), 31-37.
https://doi.org/10.1016/S0959-437X(95)90050-0
Morgan, D. O. Principles of CDK regulation. Nature 1995, 374 (6518), 131-134.
https://doi.org/10.1038/374131a0
Knighton, D. R.; Zheng, J.; Lynn, F. T. E.; Ashford, V. A.; Xuong, N.-H.; Taylor, S. S.; Sowadski, J. M. Crystal Structure of the Catalytic Subunit of Cyclic Adenosine Monophosphate-Dependent Protein Kinase. Science 1991, 253 (5018), 407-414.
https://doi.org/10.1126/science.1862342
Zhang, F.; Strand, A.; Robbins, D.; Cobb, M. H.; Goldsmith, E. J. Atomic structure of the MAP kinase ERK2 at 2.3 A resolution. Nature 1994, 367 (6465), 704-711.
https://doi.org/10.1038/367704a0
Xu, R. M.; Carmel, G.; Sweet, R. M.; Kuret, J.; Cheng, X. Crystal structure of casein kinase-1, a phosphate-directed protein kinase. EMBO J 1995, 14 (5), 1015-1023.
Owen, D. J.; Noble, M. E. M.; Garman, E. F.; Papageorigiou, A. C.; Johnson, L. N. Two structures of the catalytic domain of phosphorylase kinase: an active protein kinase complexed with substrate analogue and product. Structure 1995, 3 (5), 467-482.
https://doi.org/10.1016/S0969-2126(01)00180-0
De Bondt, H. L.; Rosenblatt, J.; Jancarik, J.; Jones, H. D.; Morgant, D. O.; Kim, S.-H. Crystal structure of cyclin-dependent kinase 2. Nature 1993, 363 (6430), 595-602.
https://doi.org/10.1038/363595a0
Taylor, S. S.; Radzio-Andzelm, E. Three protein kinase structures define a common motif. Structure 1994, 2 (5), 345-355.
https://doi.org/10.1016/S0969-2126(00)00036-8
Casimiro, M. C.; Crosariol, M.; Loro, E.; Li, Z.; Pestell, R. G. Cyclins and Cell Cycle Control in Cancer and Disease. Genes Cancers 2012, 3 (11-12), 649-657.
https://doi.org/10.1177/1947601913479022
Otto, T.; Sicinski, P. Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer 2017, 17 (2), 93-115.
https://doi.org/10.1038/nrc.2016.138
Johnson, E. F.; Stewart, K. D.; Woods, K. W.; Giranda, V. L.; Luo, Y. Pharmacological and Functional Comparison of the Polo-like Kinase Family: Insight into Inhibitor and Substrate Specificity. Biochemistry 2007, 46 (33), 9551-9563.
https://doi.org/10.1021/bi7008745
Harrington, E. A.; Bebbington, D.; Moore, J.; Rasmussen, R. K.; Ajose-Adeogun, A. O.; Nakayama, T.; Graham, J. A.; Demur, C.; Hercend, T.; Diu-Hercend, A.; Su, M.; Golec, J. M. C.; Miller, K. M. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med 2004, 10 (3), 262-267.
https://doi.org/10.1038/nm1003
Kitagawa, M.; Okabe, T.; Ogino, H.; Matsumoto, H.; Suzuki-Takahashi, I.; Kokubo, T.; Higashi, H.; Saitoh, S.; Taya, Y.; Yasuda, H. Butyrolactone I, a selective inhibitor of cdk2 and cdc2 kinase. Oncogene 1993, 8 (9), 2425-2432.
Hochegger, H.; Takeda, S.; Hunt, T. Cyclin-dependent kinases and cell-cycle transitions: does one fit all? Nat Rev Mol Cell Biol 2008, 9 (11), 910-916.
https://doi.org/10.1038/nrm2510
Ekholm, S. V.; Reed, S. I. Regulation of G1 cyclin-dependent kinases in the mammalian cell cycle. Curr Opin Cell Biol 2000, 12 (6), 676-684.
https://doi.org/10.1016/S0955-0674(00)00151-4
Hanks, S. K. Genomic analysis of the eukaryotic protein kinase superfamily: a perspective. Genome Biol 2003, 4 (5), 111.
https://doi.org/10.1186/gb-2003-4-5-111
Peyressatre, M.; Prével, C.; Pellerano, M.; Morris, C. M.; Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Targeting Cyclin-Dependent Kinases in Human Cancers: From Small Molecules to Peptide Inhibitors Simple Coumarins and Analogues in Medicinal Chemistry: Occurrence, Synthesis and Biological Activity. Cancers 2015, 7 (1), 887-916.
https://doi.org/10.3390/cancers7010179
Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Simple Coumarins and Analogues in Medicinal Chemistry: Occurrence, Synthesis and Biological Activity. Curr Med Chem 2005, 12 (8), 887-916.
https://doi.org/10.2174/0929867053507315
Ojala, T. Biological screening of plant coumarins. Academic Dissertation, University of Helsinky, Helsinki, 2001.
Hoult, J. R. S.; Payá, M. Pharmacological and biochemical actions of simple coumarins: Natural products with therapeutic potential. Gen Pharmacol Vasc Syst 1996, 27 (4), 713-722.
https://doi.org/10.1016/0306-3623(95)02112-4
Finn, G. J.; Kenealy, E.; Creaven, B. S.; Egan, D. A. In vitro cytotoxic potential and mechanism of action of selected coumarins, using human renal cell lines. Cancer Lett 2002, 183 (1), 61-68.
https://doi.org/10.1016/S0304-3835(02)00102-7
Grötz, K. A.; Wüstenberg, P.; Kohnen, R.; Al-Nawas, B.; Henneicke-von Zepelin, H. H.; Bockisch, A.; Kutzner, J.; Naser-Hijazi, B.; Belz, G. G.; Wagner, W. Prophylaxis of radiogenic sialadenitis and mucositis by coumarin/troxerutine in patients with head and neck cancer – a prospective,randomized, placebo-controlled, double-blind study. Br J Oral Maxillofac Surg 2001, 39 (1), 34-39.
https://doi.org/10.1054/bjom.2000.0459
Holbrook, A. M. P., J. A.; Labiris, R.; McDonald, H.; Douketis, J. D.; Crowther, M.; Wells, P. S. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005, 165 (10), 1095-1106.
https://doi.org/10.1001/archinte.165.10.1095
Jiménez-Orozco, F. A.; López-González, J. S.; Nieto-Rodriguez, A.; Velasco-Velázquez, M. A.; Molina-Guarneros, J. A.; Mendoza-Pati-o, N.; GarcÃa-Mondragón, M. J.; Elizalde-Galvan, P.; León-Cede-o, F.; Mandoki, J. J. Decrease of cyclin D1 in the human lung adenocarcinoma cell line A-427 by 7-hydroxycoumarin. Lung Cancer 2001, 34 (2), 185-194.
https://doi.org/10.1016/S0169-5002(01)00263-X
Yun, E.-S.; Park, S.-S.; Shin, H.-C.; Choi, Y. H.; Kim, W.-J.; Moon, S.-K. p38 MAPK activation is required for esculetin-induced inhibition of vascular smooth muscle cells proliferation. Toxicol In Vitro 2011, 25 (7), 1335-1342.
https://doi.org/10.1016/j.tiv.2011.05.001
Marshall, M. E.; Kervin, K.; Benefield, C.; Umerani, A.; Albainy-Jenei, S.; Zhao, Q.; Khazaeli, M. B. Growth-inhibitory effects of coumarin (1,2-benzopyrone) and 7-hydroxycoumarin on human malignant cell lines in vitro. J Cancer Res Clin Oncol 1994, 120 (1), S3-S10.
https://doi.org/10.1007/BF01377114
Kawaii, S.; Tomono, Y.; Ogawa, K.; Sugiura, M.; Yano, M.; Yoshizawa, Y. The antiproliferative effect of coumarins on several cancer cell lines. Anticancer Res 2001, 21 (2A), 917-923
Marshall, M.; Butler, K.; Fried, A. Phase I evaluation of coumarin (1, 2-benzopyrone) and cimetidine in patients with advanced malignancies. Mol Biother 1991, 3 (3), 170-178.
Sharma, A.; Chowdhury, R.; Dash, S.; Pallavi, B.; Shukla, P. Fast Microwave Assisted Synthesis of Pyranopyrazole Derivatives as New Anticancer Agents. Curr Microwave Chem 2016, 3 (1), 78-84.
https://doi.org/10.2174/2213335602666150116233238
Schneider, G. Prediction of drug-like properties. In Madame Curie Bioscience Database [Internet], Landes Bioscience: Austin, Texas, 2000-2013.
Schuttelkopf, A. W.; van Aalten, D. M. F. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystalogr D 2004, 60 (8), 1355-1363.
https://doi.org/10.1107/S0907444904011679
Jena, L.; Waghmare, P.; Kashikar, S.; Kumar, S.; Harinath, B. C. Computational approach to understanding the mechanism of action of isoniazid, an anti-TB drug. Int J Mycobacteriol 2014, 3 (4), 276-282.
https://doi.org/10.1016/j.ijmyco.2014.08.003
Davis, A. M.; Teague, S. J.; Schultz, J.; Ferguson, B.; Sprague Jr, G. F. Hydrogen Bonding, Hydrophobic Interactions, and Failure of the Rigid Receptor Hypothesis. Angew Chem Int Ed 1999, 38 (6), 736-749.
https://doi.org/10.1002/(SICI)1521-3773(19990315)38:6<736::AID-ANIE736>3.0.CO;2-R
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.