CDK2 is one of the most important members of Cyclin-dependent kinases. It is a
critical modulator of various oncogenic signaling pathways, and its activity is
vital for loss of proliferative control
during oncogenesis. This work has focused on developing a pharmacophore model
for CDK2 inhibitors by using a dataset of known inhibitors as a
pre-filter throughout the virtual screening and docking process. Consequently,
the best pharmacophore model was made of one hydrogen bond acceptor, and two
aromatic ring features with a high correlation value of 0.906. The validation findings
proved out that the selected model can be used as a filter to screen new
molecules like Enamine kinase hinge region directed library against CDK2.
As a result, 69 hits were subjected to molecular docking studies. Eventually,
three compounds (5909, 701 and 8397) scored good interaction
energy values and strong molecular interactions. Hence, they were identified as
leads for novel CDK2 inhibitors as anticancer drugs.
References
[1]
Cicenas, J., Kalyan, K., Sorokinas, A., et al. (2014) Highlights of the Latest Advances in Research on CDK Inhibitors. Cancers (Basel), 6, 2224-2242. https://doi.org/10.3390/cancers6042224
[2]
Cicenas, J. and Valius, M. (2011) The CDK Inhibitors in Cancer Research and Therapy. Journal of Cancer Research and Clinical Oncology, 137, 1409-1418. https://doi.org/10.1007/s00432-011-1039-4
[3]
Matthews, D.J. and Gerritsen, M.E. (2008) Targeting Protein Kinases for Cancer Therapy.
[4]
Schonbrunn, E., Betzi, S., Alam, R., et al. (2013) Development of Highly Potent and Selective Diaminothiazole Inhibitors of Cyclin-Dependent Kinases. Journal of Medicinal Chemistry, 56, 3768-3782. https://doi.org/10.1021/jm301234k
[5]
Sánchez-Martínez, C., Lallena, M.J., Sanfeliciano, S.G. and de Dios, A. (2019) Cyclin Dependent Kinase (CDK) Inhibitors as Anticancer Drugs: Recent Advances (2015-2019). Bioorganic and Medicinal Chemistry Letters, 29, Article ID: 126637. https://doi.org/10.1016/j.bmcl.2019.126637
[6]
Li, Y., Zhang, J., Gao, W., et al. (2015) Insights on Structural Characteristics and Ligand Binding Mechanisms of CDK2. International Journal of Molecular Sciences, 16, 9314-9340. https://doi.org/10.3390/ijms16059314
[7]
Oranit Dror, A.S.-P., Nussinov, R. and Wolfson, H.J. (2006) Predicting Molecular Interactions in Silico: I. An Updated Guide to Pharmacophore Identification and Its Applications to Drug Design. Frontiers in Medicinal Chemistry, 3, 551-584. https://doi.org/10.2174/978160805206610603010551
[8]
Ferreira, L., dos Santos, R., Oliva, G. and Andricopulo, A. (2015) Molecular Docking and Structure-Based Drug Design Strategies. Molecules, 20, 13384-13421. https://doi.org/10.3390/molecules200713384
[9]
Caporuscio, F. and Tafi, A. (2011) Pharmacophore Modelling: A Forty Year Old Approach and Its Modern Synergies. Current Medicinal Chemistry, 18, 2543-2553. https://doi.org/10.2174/092986711795933669
[10]
Vuorinen, A. and Schuster, D. (2015) Methods for Generating and Applying Pharmacophore Models as Virtual Screening Filters and for Bioactivity Profiling. Methods, 71, 113-134. https://doi.org/10.1016/j.ymeth.2014.10.013
[11]
Yves Pommier, C.M. and Neamati, N. (2000) Retroviral Integrase Inhibitors Year 2000: Update and Perspectives. Antiviral Research, 47, 139-148. https://doi.org/10.1016/S0166-3542(00)00112-1
[12]
Hecker, E., Andrea, T., et al. (2002) Use of Catalyst Pharmacophore Models for Screening of Large Combinatorial Libraries. The Journal for Chemical Information and Computer Scientists, 42, 1204-1211. https://doi.org/10.1021/ci020368a
[13]
Toba, S., Maynard, A.J. and Sutter, J. (2006) Using Pharmacophore Models to Gain Insight into Structural Binding and Virtual Screening: An Application Study with CDK2 and Human DHFR. Journal of Chemical Information and Modeling, 46, 728-735. https://doi.org/10.1021/ci050410c
[14]
Richardson, C.M., Williamson, D.S., Parratt, M.J., et al. (2006) Triazolo[1,5-a]pyrimidines as Novel CDK2 Inhibitors: Protein Structure-Guided Design and SAR. Bioorganic and Medicinal Chemistry Letters, 16, 1353-1357. https://doi.org/10.1016/j.bmcl.2005.11.048
[15]
Lin, S.-K. (2000) Pharmacophore Perception, Development and Use in Drug Design. Edited by Osman F. Güner. Molecules, 5, 987-989. https://doi.org/10.3390/50700987
[16]
Chohan, T., Qian, H., Pan, Y. and Chen, J.-Z. (2014) Cyclin-Dependent Kinase-2 as a Target for Cancer Therapy: Progress in the Development of CDK2 Inhibitors as Anti-Cancer Agents. Current Medicinal Chemistry, 22, 237-263. https://doi.org/10.2174/0929867321666141106113633
[17]
De Azevedo Jr., W.F. and Kim, S.H. (1997) Inhibition of Cyclin-Dependent Kinases by Purine Analogues: Crystal Structure of Human CDK2 Complexed with Roscovitine. European Journal of Biochemistry, 526, 518-526. https://doi.org/10.1111/j.1432-1033.1997.0518a.x
Harrison, L.R., Ottley, C.J., Pearson, D.G., et al. (2009) The Kinase Inhibitor O6-Cyclohexylmethylguanine (NU2058) Potentiates the Cytotoxicity of Cisplatin by Mechanisms That Are Independent of Its Effect upon CDK2. Biochemical Pharmacology, 77, 1586-1592. https://doi.org/10.1016/j.bcp.2009.02.018
[20]
Dreyer, M.K., Borcherding, D.R., Dumont, J.A., et al. (2001) Crystal Structure of Human Cyclin-Dependent Kinase 2 in Complex with the Adenine-Derived Inhibitor H717. Journal of Medicinal Chemistry, 44, 524-530. https://doi.org/10.1021/jm001043t
[21]
Schulze-gahmen, U., Brandsen, J., Jones, H.D., Morgan, D., Meijer, L. and Ve, J. (1995) Multiple Modes of Ligand Recognition: Crystal Structures of Cyclin-Dependent Protein Kinase 2 in Complex with ATP and Two Inhibitors, Olomoucine and Isopentenyladenine. Proteins: Structure, Function, and Bioinformatics, 22, 378-391. https://doi.org/10.1002/prot.340220408
[22]
Misra, R.N., Xiao, H.Y., Kim, K.S., Lu, S., Han, W.C., Barbosa, S.A., Hunt, J.T., Rawlins, D.B., Shan, W., Ahmed, S.Z., Qian, L., Chen, B.C., Zhao, R., Bednarz, M.S., Kellar, K.A., Mulheron, J.G., Batorsky, R., Roongta, U., Kamath, A., Kimball, S.D., et al. (2004) N-(Cycloalkylamino)acyl-2-aminothiazole Inhibitors of Cyclin-Dependent Kinase 2. N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (BMS-387032), a Highly Efficacious and Selective Antitumor Agent. Journal of Medicinal Chemistry, 47, 1719-1728. https://doi.org/10.1021/jm0305568
[23]
Arris, C.E., Boyle, F.T., Calvert, A.H., et al. (2000) Identification of Novel Purine and Pyrimidine Cyclin-Dependent Kinase Inhibitors with Distinct Molecular Interactions and Tumor Cell Growth Inhibition Profiles. Journal of Medicinal Chemistry, 43, 2797-2804. https://doi.org/10.1021/jm990628o
[24]
Finlay, M.R.V., Acton, D.G., Andrews, D.M., et al. (2008) Imidazole Piperazines: SAR and Development of a Potent Class of Cyclin-Dependent Kinase Inhibitors with a Novel Binding Mode. Bioorganic & Medicinal Chemistry Letters, 18, 4442-4446. https://doi.org/10.1016/j.bmcl.2008.06.027
[25]
Eisenbrand, G., Hippe, Æ.F. and Jakobs, Æ.S. (2004) Molecular Mechanisms of Indirubin and Its Derivatives: Novel Anticancer Molecules with Their Origin in Traditional Chinese Phytomedicine. Journal of Cancer Research and Clinical Oncology, 130, 627-635. https://doi.org/10.1007/s00432-004-0579-2
[26]
Brogi, S., Kladi, M., Vagias, C., Papazafiri, P., Roussis, V. and Tafi, A. (2009) Pharmacophore Modeling for Qualitative Prediction of Antiestrogenic Activity. Journal of Chemical Information and Modeling, 49, 2489-2497. https://doi.org/10.1021/ci900254b
[27]
P, S.K., Singh, A. and Sharma, S. (2015) Ligand Based Pharmacophore Modeling, Virtual Screening and Molecular Docking for Identification of Novel CYP51 Inhibitors. Abstract Dataset Collection. ChemInform, 1, 2.
[28]
Ramachandran, V., Padmanaban, E. and Ponnusamy, K. (2016) RSC Advances Pharmacophore Based Virtual Screening for Identification of Marine Bioactive Compounds as Inhibitors against Macrophage Infectivity Potentiator (Mip) Protein of Chlamydia trachomatis. RSC Advances, 6, 18946-18957. https://doi.org/10.1039/C5RA24999F
[29]
Niu, M., Dong, F., Tang, S., et al. (2013) Pharmacophore Modeling and Virtual Screening for the Discovery of New Type 4 cAMP Phosphodiesterase (PDE4) Inhibitors. PLoS ONE, 8, e82360. https://doi.org/10.1371/journal.pone.0082360
[30]
Vazquez, J., Lopez, M., Gibert, E., Herrero, E. and Luque, F.J. (2020) Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches. Molecules, 25, 4723. https://doi.org/10.3390/molecules25204723
[31]
Wu, G., Robertson, D.H., Iii, C.L.B. and Vieth, M. (2003) Detailed Analysis of Grid-Based Molecular Docking: A Case Study of CDOCKER—A CHARMm-Based MD Docking Algorithm. Journal of Computational Chemistry, 24, 1549-1562. https://doi.org/10.1002/jcc.10306
[32]
Kaserer, T., Beck, K.R., Akram, M., Odermatt, A. and Schuster, D. (2015) Pharmacophore Models and Pharmacophore-Based Virtual Screening: Concepts and Applications Exemplified on Hydroxysteroid Dehydrogenases. Molecules, 20, 22799-22832. https://doi.org/10.3390/molecules201219880
[33]
Singh, A.K., Raj, V. and Saha, S. (2017) Indole-Fused Azepines and Analogues as Anticancer Lead Molecules: Privileged Findings and Future Directions. European Journal of Medicinal Chemistry, 142, 244-265. https://doi.org/10.1016/j.ejmech.2017.07.042
