Docking and quantitative structure–activity relationship studies for imidazo[1,2-a]pyrazines as inhibitors of checkpoint kinase-1
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We have performed docking of imidazo[1,2-a]pyrazines complexed with checkpoint kinase1 (Chk1) to better understand the structural requirements and preferred conformations of these inhibitors. The study was performed on a selected set of 33 compounds with variation in structure and activity. In addition, the predicted inhibitor concentrations (IC50) of the imidazo[1,2-a]pyrazines as Chk1 inhibitors were obtained by comparative molecular similarity analysis (CoMSIA). The best CoMSIA model included electrostatic and hydrophobic fields, had a good Q 2 value of 0.589, and adequately predicted the compounds contained in the test set. Furthermore, plots of the CoMSIA fields allowed conclusions to be drawn for the selection of suitable inhibitors.
KeywordsCheckpoint kinase-1 inhibitors Molecular docking Quantitative structure–activity relationships CoMSIA
Julio Caballero thanks “Becas Universidad de Talca” for financial support through doctoral fellowship. Part of this work has been supported by Fondecyt, Grant 11090431, Proyecto interno DI-13-10/R, Universidad Andres Bello.
- Alzate-Morales JH, Caballero J, Vergara-Jaque A, González-Nilo FD (2009) Insights into the structural basis of N2 and O6 substituted guanine derivatives as cyclin-dependent kinase 2 (CDK2) inhibitors: prediction of the binding modes and potency of the inhibitors by docking and ONIOM calculations. J Chem Inf Model 49:886–899. doi: 10.1021/ci8004034 PubMedCrossRefGoogle Scholar
- Alzate-Morales JH, Vergara-Jaque A, Caballero J (2010) Computational study on the interaction of N1 substituted pyrazole derivatives with B-Raf kinase: an unusual water wire hydrogen-bond network and novel interactions at the entrance of the active site. J Chem Inf Model 50:1101–1112. doi: 10.1021/ci100049h PubMedCrossRefGoogle Scholar
- Caballero J, Vergara-Jaque A, Fernández M, Coll D (2009) Docking and quantitative structure–activity relationship studies for sulfonyl hydrazides as inhibitors of cytosolic human branched-chain amino acid aminotransferase. Mol Divers 13:493–500. doi: 10.1007/s11030-009-9140-1 PubMedCrossRefGoogle Scholar
- Garriga M, Caballero J (2011) Insights into the structure of urea-like compounds as inhibitors of the juvenile hormone epoxide hydrolase (JHEH) of the tobacco hornworm Manduca sexta: analysis of the binding modes and structure–activity relationships of the inhibitors by docking and CoMFA calculations. Chemosphere 82:1604–1613. doi: 10.1016/j.chemosphere.2010.11.048 PubMedCrossRefGoogle Scholar
- Halgren TA (1996) Merck molecular force field. V. Extension of MMFF94 using experimental data, additional computational data, and empirical rules. J Comput Chem 17:616–641. doi: 10.1002/(SICI)1096-987X(199604)17:5/6<616:AID-JCC5>3.0.CO;2-X CrossRefGoogle Scholar
- Janetka JW, Ashwell S, Zabludoff S, Lyne P (2007) Inhibitors of checkpoint kinases: from discovery to the clinic. Curr Opin Drug Dicov Develop 10:473–486Google Scholar
- Lagos CF, Caballero J, Gonzalez-Nilo FD, Pessoa-Mahana CD, Perez-Acle T (2008) Docking and quantitative structure–activity relationship studies for the bisphenylbenzimidazole family of non-nucleoside inhibitors of HIV-1 reverse transcriptase. Chem Biol Drug Des 72:360–369. doi: 10.1111/j.1747-0285.2008.00716.x PubMedCrossRefGoogle Scholar
- Matthews TP, Klair S, Burns S, Boxall K, Cherry M, Fisher M, Westwood IM, Walton MI, McHardy T, Cheung K-MJ, Van Montfort R, Williams D, Aherne GW, Garrett MD, Reader J, Collins I (2009) Identification of inhibitors of checkpoint kinase 1 through template screening. J Med Chem 52:4810–4819. doi: 10.1021/jm900314j PubMedCrossRefGoogle Scholar
- Matthews TP, McHardy T, Klair S, Boxall K, Fisher M, Cherry M, Allen CE, Addison GJ, Ellard J, Aherne GW, Westwood IM, van Montfort R, Garrett MD, Reader JC, Collins I (2010) Design and evaluation of 3, 6-di(hetero)aryl imidazo[1, 2-a]pyrazines as inhibitors of checkpoint and other kinases. Bioorg Med Chem Lett 20:4045–4049. doi: 10.1016/j.bmcl.2010.05.096 PubMedCrossRefGoogle Scholar
- Nemethy G, Gibson KD, Palmer KA, Yoon CN, Paterlini G, Zagari A, Rumsey S, Scheraga HA (1992) Energy parameters in polypeptides. 10. Improved geometrical parameters and nonbonded interactions for use in the ECEPP/3 algorithm, with application to proline-containing peptides. J Phys Chem 96:6472–6484. doi: 10.1021/j100194a068 CrossRefGoogle Scholar