Abstract
Dyrk family enzymes are essential components of important signaling casades in the pathophysiology of cancer and Alzheimer’s disease. Especially, Dyrk2 biological expression levels regulate key signaling processes in these diseases. In the present work, a pharmacophore-based 3D-QSAR model was generated for a series of leucettine analogs possessing Dyrk2 inhibitory activity. Developed pharmacophore model contains four hydrogen bond acceptors (A) and one hydrophobic aromatic ring (R). These are crucial molecular fingerprints which predict binding efficacy of high affinity and low affinity ligands to the Dyrk2 enzyme. These pharmacophoric features point toward key structural requirements of leucettines for potent Dyrk2 inhibition. Furthermore, a biological correlation between pharmacophore hypothesis-based 3D-QSAR variables and functional fingerprints of leucettines responsible for the receptor binding was observed. Alignment of the developed model with Dyrk2 crystal structure indicated importance of A3 and A4 H-bond accetor sites, which are involved in the important interactions with Leu231A and Lys178A residues of the active site. Excellent statistical results of QSAR model such as good correlation coefficient (r 2 > 0.95), higher F value (F > 106), and excellent predictive power (Q 2 > 0.7) with low standard deviation (SD < 0.2) strongly suggest that the developed model is good for the future prediction of Dyrk2 inhibitory activity of new leucettine analogs.
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Abbreviations
- 3D-QSAR:
-
3-Dimensional quantitative structure–activity relationship
- Dyrk1A:
-
Dual-specificity tyrosine-phosphorylated and regulated kinase 1a
- Dyrk2:
-
Dual-specificity tyrosine-phosphorylated and regulated kinase 2
- PLS:
-
Partial least square
- RMSD:
-
Relative mean square deviation
- RMSE:
-
Root-mean-square error
- SD:
-
Standard deviation
- r 2 :
-
Correlation coefficient
- Q 2 :
-
Correlation coefficient for test set
References
Bharate SB, Yadav RR, Battula S, Vishwakarma RA (2012a) Meridianins: marine-derived potent kinase inhibitors. Mini Rev Med Chem 12:618–631
Bharate SB, Manda S, Mupparapu N, Battini N, Vishwakarma RA (2012b) Chemistry and biology of fascaplysin, a potent marine-derived CDK-4 inhibitor. Mini Rev Med Chem 12:650–664
Bharate SB, Manda S, Joshi P, Singh B, Vishwakarma RA (2012c) Total synthesis and anti-cholinesterase activity of marine-derived bis-indole alkaloid fascaplysin. Med Chem Commun 3:1098–1103
Bharate SB, Yadav RR, Vishwakarma RA (2013a) QSAR and pharmacophore study of Dyrk1A inhibitory meridianin analogs as potential agents for treatment of neurodegenerative diseases. Med Chem 9:152–161
Bharate SB, Singh B, Bharate JB, Jain SK, Meena S, Vishwakarma RA (2013b) QSAR and pharmacophore modeling of N-acetyl-2-aminobenzothiazole class of phosphoinositide-3-kinase-alpha inhibitors. Med Chem Res 22:890–899
Cuny GD, Robin M, Ulyanova NP, Patnaik D, Pique V, Casano G, Liu J-F, Lin X, Xian J, Glicksman MA, Stein RL, Higgins JMG (2010) Structure–activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors. Bioorg Med Chem Lett 20:3491–3494
Cuny GD, Ulyanova NP, Patnaik D, Liu J-F, Lin X, Auerbach K, Ray SS, Xian J, Glicksman MA, Stein RL, Higgins JM (2012) Structure–activity relationship study of beta-carboline derivatives as haspin kinase inhibitors. Bioorg Med Chem Lett 22:2015–2019
Debdab M, Carreaux F, Renault S, Soundararajan M, Fedorov O, Filippakopoulos P, Lozach O, Babault L, Tahtouh T, Baratte B, Ogawa Y, Hagiwara M, Eisenreich A, Rauch U, Knapp S, Meijer L, Bazureau JP (2011) Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: modulation of alternative pre-RNA splicing. J Med Chem 54:4172–4186
Dixon SL, Smondyrev AM, Knoll EH, Rao SN, Shaw DE, Friesner RA (2006a) PHASE: a new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. Methodology and preliminary results. J Comput Aided Mol Des 20:647–671
Dixon SL, Smondyrev AM, Rao SN (2006b) PHASE: a novel approach to pharmacophore modeling and 3D database searching. Chem Biol Drug Des 67:370–372
Ferrer I, Barrachina M, Puig B, Lagran MMD, Marti E, Avila J, Dierssen M (2005) Constitutive Dyrk1A is abnormally expressed in Alzheimer disease, Down syndrome, Pick disease, and related transgenic models. Neurobiol Dis 20:392–400
Filippakopoulos P, Myrianthopoulos V, Kritsanida M, Magiatis P, Skaltsounis AL, Krojer T, Gileadi O, Hapka E, Fedorov O, Berridge G, Wang J, Shrestha L, Vollmar M, Von Delft F, Arrowsmith CH, Edwards A, Weigelt J, Bountra C, Mikros E, Knapp S (2010) Crystal structure of dual-specificity tyrosine phosphorylation regulated kinase 2 (Dyrk2) in complex with an indirubin ligand. RCSB. doi:10.2210/pdb3kvw/pdb
Laguna A, Aranda S, Barallobre MJ, Barhoum R, Fernández E, Fotaki V, Delabar JM, de la Luna S, de la Villa P, Arbonés ML (2008) The protein kinase DYRK1A regulates caspase-9-mediated apotposis during retina development. Dev Cell 15:841–853
Lochhead PA, Sibbet G, Morrice N, Cleghon V (2005) Activation-loop autophosphorylation is mediated by a novel transitional intermediate form of DYRKs. Cell 121:925–936
Maddika S, Chen J (2009) Protein kinase Dyrk2 is a scaffold that facilitates assembly of an E3 ligase. Nat Cell Biol 11:409–419
Miller CT, Aggarwal S, Lin TK, Dagenais SL, Contreras JI, Orringer MB, Glover TW, Beer DG, Lin L (2003) Amplification and overexpression of the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 2 (DYRK2) gene in esophageal and lung adenocarcinomas. Cancer Res 63:4136–4143
Park J, Song WJ, Chung KC (2009) Function and regulation of Dyrk1A: towards understanding Down syndrome. Cell Mol Life Sci 66:3235–3240
Tahtouh T, Elkins JM, Filippakopoulos P, Soundararajan M, Burgy G, Durieu E, Cochet C, Schmid RS, Lo DC, Delhommel F, Oberholzer AE, Pearl LH, Carreaux F, Bazureau JP, Knapp S, Meijer L (2012) Selectivity, cocrystal structures, and neuroprotective properties of leucettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid leucettamine B. J Med Chem 55:9312–9330
Taira N, Nihira K, Yamaguchi T, Miki Y, Yoshida K (2007) Dyrk2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage. Mol Cell 25:725–738
Yamashita S, Chujo M, Moroga T, Anami K, Tokuishi K, Miyawaki M, Kawano Y, Takeno S, Yamamoto S, Kawahara K (2009) Dyrk2 expression may be a predictive marker for chemotherapy in non-small cell lung cancer. Anticancer Res 29:2753–2757
Yoshida K (2008) Role for Dyrk family kinases on regulation of apoptosis. Biochem Pharmacol 76:1389–1394
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Authors are thankful to Schrodinger Inc. for providing license Schrodinger molecular modeling software.
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Bahl, A., Joshi, P., Bharate, S.B. et al. Pharmacophore modeling and 3D-QSAR studies of leucettines as potent Dyrk2 inhibitors. Med Chem Res 23, 1925–1933 (2014). https://doi.org/10.1007/s00044-013-0767-1
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DOI: https://doi.org/10.1007/s00044-013-0767-1