Email this article A quantitative structure-activity relationship (QSAR) study of some diaryl urea derivatives of B-RAF inhibitors
Abstract
In the current study, both ligand-based molecular docking and receptor-based quantitative structure activity relationships (QSAR) modeling were performed on 35 diaryl urea derivative inhibitors of V600EB-RAF. In this QSAR study, a linear (multiple linear regressions) and a nonlinear (partial least squares least squares support vector machine (PLS-LS-SVM)) were used and compared. The predictive quality of the QSAR models was tested for an external set of 31 compounds, randomly chosen out of 35 compounds. The results revealed the more predictive ability of PLS-LS-SVM in analysis of compounds with urea structure. The selected descriptors indicated that size, degree of branching, aromaticity, and polarizability affected the inhibition activity of these inhibitors. Furthermore, molecular docking was carried out to study the binding mode of the compounds. Docking analysis indicated some essential H-bonding and orientations of the molecules in the active site.
the solubility and dissolution rate of ABZ were increased 1.8-2.6 folds and 3-25 folds, respectively. Unexpectedly, SLS decreased the solubility index of drug powder even lower than the unprocessed drug which was attributed to drug-SLS ionic interaction as depicted from Fourier transform infrared spectroscopy. It was concluded that by applying the facile, one-step, industrially scalable technique and the use of small amounts of excipient (only 4% of the formulation), a great improvement (21 folds) in dissolution rate of ABZ was achieved. This finding may be used in the pharmaceutical industries for the formulation of therapeutically efficient dosage forms of class II and IV drugs classified in biopharmaceutical classification system.
Keywords
Full Text:
PDFReferences
Leicht DT, Balan V, Kaplun A, Singh-Gupta V, Kaplun L, Dobson M, et al. RAF kinases: function, regulation and role in human cancer. Biochim Biophys Acta. 2007;1773(8):1196-1212.
Peyssonnaux C, Eychene A. The RAF/MEK/ERK pathway: new concepts of activation. Biol Cell. 2001;93(1-2):53-62.
Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3(6):459-465.
Roskoski R Jr. RAF protein-serine/threonine kinases: Structure and regulation. Biochem Biophys Res Commun. 2010;399(3):313-317.
Hagemann C, Rapp UR. Isotype-specific functions of RAF kinases. Exp Cell Res. 1999;253(1):34-46.
Huang T, Zhuge J, Zhang WW. Sensitive detection of BRAFV600E mutation byAmplification Refractory Mutation System (ARMS)-PCR. Biomark Res. 2013;1:3.
Lee B, Mukhi N, Liu D. Current management and novel agents for malignant melanoma. J Hematol Oncol. 2012;5:3.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-954.
Domingo E, Laiho P, Ollikainen M, Pinto M, Wang L, French AJ, et al. BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet. 2004;41(9):664-668.
Rahman MA, Salajegheh A, Smith RA, Lam AK. B-RAF mutation: A key player in molecular biology of cancer. Exp Mol Pathol. 2013;95(3):336-342.
Li HF, Lu T, Zhu T, Jiang YJ, Rao SS, Hu LY, et al. Virtual screening for RAF-1 kinase inhibitors based on pharmacophore model of substituted ureas. Eur J Med Chem. 2009;44(3):1240-1249.
Wong KK. Recent developments in anti-cancer agents targeting the Ras/RAF/ MEK/ERK Pathway. Recent Pat Anticancer Drug Discov. 2009;4(1):28-35.
Pratilas CA, Solit DB. Targeting the mitogen-activated protein kinase pathway: physiological feedback and drug response. Clin Cancer Res. 2010;16(13):3329-3334.
Stenner F, Chastonay R, Liewen H, Haile SR, Cathomas R, Rothermundt C, et al. A pooled analysis of sequential therapies with soRAFenib and sunitinib in metastatic renal cell carcinoma. Oncology. 2012;82(6):333-340.
Wu J, Zhu AX. Targeting insulin-like growth factor axis in hepatocellular carcinoma. J Hematol Oncol. 2011;4:30.
Zhang S. Computer-Aided Drug Discovery and Development. Methods Mol Biol. 2011;716:23-38.
Hansch C, Hoekman D, Gao H. Comparative QSAR: toward a deeper understanding of chemicobiological interactions. Chem Rev. 1996;96(3):1045-1076.
Foroumadi A, Sakhteman A, Sharifzadeh Z, Mohammadhosseini N, Hemmateenejad B, Moshafi MH, et al. Synthesis, antituberculosis activity and QSAR study of some novel 2-(nitroaryl)-5-(nitrobenzylsulfinyl and sulfonyl)-1,3,4-thiadiazolederivatives. Daru. 2007;15(4):218-226.
Pirard B. Computational methods for the identification and optimisation of high quality leads. Comb Chem High Throughput Screen.2004;7(4):271-280.
Cavasotto CN, Orry AJ. Ligand docking and structure-based virtual screening in drug discovery. Curr Top Med Chem. 2007;7(10):1006-1014.
Kitchen DB, Decornez H, Furr JR, Bajorath J. Docking and scoring in virtual screening for drug discovery: methods and applications. Nat Rev Drug Discov. 2004;3(11):935-949.
Khoshneviszadeh M, Sakhteman A. Exploring quantitative structure–activity relationship (QSAR) models for some biologically active catechol structures using PC-LS-SVM and PC-ANFIS. J Appl Biol Chem. 2016;59(3):433-441.
Menard D, Niculescu-Duvaz I, Dijkstra HP, Niculescu-Duvaz D, Suijkerbuijk BM, Zambon A, et al. Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring. J Med Chem. 2009;52(13):3881-3891.
Tetko IV, Sushko I, Pandey AK, Zhu H, Tropsha A, Papa E, et al. Critical assessment of QSAR models of environmental toxicity against Tetrahymena pyriformis: focusing on applicability domain and overfitting by variable selection. J Chem Inf Model. 2008;48(9):1733-1746.
Wallace AC, Laskowski RA, Thornton JM. LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng. 1995;8:127-134.
Refbacks
- There are currently no refbacks.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.