Docking and quantitative structure-activity relationship studies for 3-fluoro-4-(pyrrolo[2,1- f][1,2,4]triazin-4-yloxy)aniline, 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline, and 4-(4-amino-2-fluorophenoxy)-2-pyridinylamine derivatives as c-Met kinase inhibitors

Caballero, Julio; Quiliano, Miguel; Alzate-Morales, Jans; Zimic, Mirko; Deharo, Eric

We have performed docking of 3-fluoro-4-(pyrrolo[2,1- f][1,2,4]triazin-4-yloxy)aniline (FPTA), 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline (FPPA), and 4-(4-amino-2-fluorophenoxy)-2-pyridinylamine (AFPP) derivatives complexed with c-Met kinase to study the orientations and preferred active conformations of these inhibitors. The study was conducted on a selected set of 103 compounds with variations both in structure and activity. Docking helped to analyze the molecular features which contribute to a high inhibitory activity for the studied compounds. In addition, the predicted biological activities of the c-Met kinase inhibitors, measured as IC values were obtained by using quantitative structure-activity relationship (QSAR) methods: Comparative molecular similarity analysis (CoMSIA) and multiple linear regression (MLR) with topological vectors. The best CoMSIA model included steric, electrostatic, hydrophobic, and hydrogen bond-donor fields; furthermore, we found a predictive model containing 2D-autocorrelation descriptors, GETAWAY descriptors (GETAWAY: Geometry, Topology and Atom-Weight AssemblY), fragment-based polar surface area (PSA), and MlogP. The statistical parameters: cross-validate correlation coefficient and the fitted correlation coefficient, validated the quality of the obtained predictive models for 76 compounds. Additionally, these models predicted adequately 25 compounds that were not included in the training set.

AMINO acids; CHEMICAL inhibitors; QSAR models; REGRESSION analysis; ORGANIC compounds

Journal of Computer-Aided Molecular Design, 2011, Vol 25, Issue 4, p349

0920-654X

Academic Journal

10.1007/s10822-011-9425-1