Abstract
A successful 3D-QSAR study has been performed for amino-substituted N-acyl and N-aroylpyrazolines as B-Raf kinase inhibitors by means of a common five-point pharmacophore model. In this study, highly predictive 3D-QSAR models have been developed for B-Raf kinase inhibition and pERK inhibition using AADRR-2 and AADRR-6 hypothesis, respectively. The best models showed statistically outstanding values of 0.97, 0.95 and 0.91, 0.87 for r 2 and q 2 for AADRR-2 and AADRR-6 hypothesis, respectively. The validation of the PHASE model was done by dividing the dataset into training and test set. From the QSAR model, it can implicated that electron-withdrawing and hydrophobic groups are not advantageous for both enzymatic and cellular activities. However, H-bond donor characteristic is favorable for cellular inhibition and unfavorable for enzymatic inhibition. Based on the findings of the 3D-QSAR study, novel and promising compounds for B-Raf kinase inhibition can be synthesized.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ahmad T, Eisen T (2004) Kinase inhibition with BAY 43–9006 in renal cell carcinoma. Clin Cancer Res 10:6388S–6392S
Anna MA, Marco T, Antonino L (2010) 3D-QSAR pharmacophore modeling and in silico screening of new Bcl-xl inhibitors. Eur J Med Chem 45:4774–4782
Aronov AM, Baker C, Bemis GW, Cao J, Chen G, Ford PJ, Germann UA, Green J, Hale MR, Jacobs M, Janetka JW, Maltais F, Martinez-Botella G, Namchuk MN, Straub J, Tang Q, Xie X (2007) Flipped out: structure-guided design of selective pyrazolylpyrrole ERK inhibitors. J Med Chem 50:1280–1287
Christopher B, Duffey MO, Gould AE, Kulkarni B, Liu JX, Menon S, Nagayoshi M, Vos TJ, Williams J (2010) Discovery and optimization of N-acyl and N-aroylpyrazolines as B-Raf kinase inhibitors. Bioorg Med Chem Lett 20(16):4795–4799
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954
Dixon SL, Smondyrev AM, Knoll EH, Rao SN, Shaw DE, Friesner RA (2006) 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
Hingorani SR, Jacobetz MA, Robertson GP, Herlyn M, Tuveson DA (2003) Suppression of BRAF(V599E) in human melanoma abrogates transformation. Cancer Res 63:5198–5202
Hoeflich KP, Gray DC, Eby MT, Tien JY, Wong L, Bower J, Gogineni A, Zha J, Cole MJ, Stern HM, Murray LJ, Davis DP, Seshagiri S (2006) Oncogenic BRAF is required for tumor growth and maintenance in melanoma models. Cancer Res 66(2):999–1006
Karasarides M, Chiloeches A, Hayward R, Niculescu-Duvaz D, Scanlon I, Friedlos F, Ogilvie L, Hedley D, Martin J, Marshall CJ, Springer CJ, Marais R (2004) B-RAF is a therapeutic target in melanoma. Oncogene 23(37):6292–6298
LigPrep (2009) Version 2.3, Schrödinger, LLC, New York
MacroModel (2009) Version 9.7, Schrödinger, LLC, New York
Mahipal XX, Tanwar OP, Karthikeyan C, Moorthy NSHN, Trivedi P (2010) 3D-QSAR of aminophenyl benzamide derivatives as histone deacetylase inhibitors. Med Chem 6:277–285
Ménard D, Niculescu-Duvaz I, Dijkstra HP, Niculescu-Duvaz D, Suijkerbuijk BM, Zambon A, Nourry A, Roman E, Davies L, Manne HA, Friedlos F, Kirk R, Whittaker S, Gill A, Taylor RD, Marais R, Springer CJ (2009) Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring. J Med Chem 52:3881–3891
Muddassar M, Pasha FA, Yoo KH, Lee SH, Cho SJ (2008) Docking and quantum mechanics-guided CoMFA analysis of b-RAF inhibitors. Bull Korean Chem Soc 29:1499–1504
Niculescu-Duvaz I, Roman E, Whittaker SR, Friedlos F, Kirk R, Scanlon IJ, Davies LC, Niculescu-Duvaz D, Marais R, Springer CJ (2008) Novel inhibitors of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) based on a 2,6-disubstituted pyrazine scaffold. J Med Chem 51:3261–3274
Pasha FA, Srivastava HK, Beg Y, Singh PP (2006) DFT based electrophilicity index and QSAR study of phenols as anti Leukaemia agent American. J Immunol 2(1):23–28
Pasha FA, Muddassar M, Neaz MM, Cho SJ (2009) Pharmacophore and docking-based combined in silico study of KDR inhibitors. J Mol Graph Model 28:54–61
Ramurthy S, Subramanian S, Aikawa M, Amiri P, Costales A, Dove J, Fong S, Jansen JM, Levine B, Ma S, McBride CM, Michaelian J, Pick T, Poon DJ, Girish S, Shafer CM, Stuart D, Sung L, Renhowe PA (2008) Design and synthesis of orally bioavailable Benzimidazoles as Raf kinase inhibitors. J Med Chem 51:7049–7052
Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogenactivated protein kinase cascade for the treatment of cancer. Oncogene 26(22):3291–3310
Robinson MJ, Cobb MH (1997) Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 9:180–186
Sachin SN, Mariam SD (2007) Pharmacophore refinement and 3D-QSAR studies of histamine H3 antagonists. QSAR Comb Sci 26:744–753
Samantha L, Cesare M, Aleksey K, Mattia S, Stefano M, Elena C, Dorotea R, Alessandro C (2008) SAR and QSAR study on 2-aminothiazole derivatives, modulators of transcriptional repression in Huntington’s disease. Bioorg Med Chem 16:5695–5703
PHASE-3.1, Schrödinger, LLC (2009) New York
Shah UA, Deokar HS, Kadam SS, Kulkarni VM (2010) Pharmacophore generation and atom-based 3D-QSAR of novel 2-(4-methylsulfonylphenyl)pyrimidines as COX-2 inhibitors. Mol Divers 14:559–568
Singh PP, Srivastava HK, Pasha FA (2004) DFT-based QSAR study of testosterone and its derivatives. Bioorg Med Chem 12:171–177
Srivastava HK, Pasha FA, Mishra SK, Singh PP (2009) Novel applications of atomic softness and QSAR study of testosterone derivatives. Med Chem Res 18:455–466
Tanwar OP, Saha R, Alam MM, Akhtar M (2010) 3D-QSAR of amino-substituted pyrido[3,2B]pyrazinones as PDE-5 inhibitors. Med Chem Res. doi:10.1007/s00044-010-9523-y
Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, Sproesser K, Li L, Smalley KS, Fong D, Zhu YL, Marimuthu A, Nguyen H, Lam B, Liu J, Cheung I, Rice J, Suzuki Y, Luu C, Settachatgul C, Shellooe R, Cantwell J, Kim SH, Schlessinger J, Zhang KY, West BL, Powell B, Habets G, Zhang C, Ibrahim PN, Hirth P, Artis DR, Herlyn M, Bollag G (2008) Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci USA 105(8):3041–3046
Viney L, Rajendra K, Jagmohan SS, Rajendra K, Narasingapuram AK, Vitukudi NB (2008) QSAR models for prediction of glycogen synthase kinase-3b inhibitory activity of indirubin derivatives. QSAR Comb Sci 27:718–728
Zambon A, Ménard D, Suijkerbuijk BM, Niculescu-Duvaz I, Whittaker S, Niculescu-Duvaz D, Nourry A, Davies L, Manne HA, Lopes F, Preece N, Hedley D, Ogilvie LM, Kirk R, Marais R, Springer CJ (2010) Novel hinge binder improves activity and pharmacokinetic properties of BRAF inhibitors. J Med Chem 53:5639–5655
Acknowledgments
The authors wish to acknowledge the team of Schrödinger for providing software facility, UGC for financial support, and Janab Abdul Mueed Sb. for providing infrastructure and facility to carry out this work.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tanwar, O., Marella, A., Shrivastava, S. et al. Pharmacophore model generation and 3D-QSAR analysis of N-acyl and N-aroylpyrazolines for enzymatic and cellular B-Raf kinase inhibition. Med Chem Res 22, 2174–2187 (2013). https://doi.org/10.1007/s00044-012-0210-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-012-0210-z