2D Autocorrelation, CoMFA, and CoMSIA modeling of protein tyrosine kinases' inhibition by substituted pyrido[2,3-d]pyrimidine derivatives

Caballero, J; Fernandez, M. ; Saavedra M.; Gonzalez-Niloa, FD

Abstract

2D Autocorrelation, comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) were undertaken for a series of substituted pyrido[2,3-d]pyrimidine derivatives to correlate platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and c-Src tyrosine kinases' inhibition with 2D and 3D structural properties of 22 known compounds. QSAR models with considerable internal as well as external predictive ability were obtained. The relevant 2D autocorrelation descriptors for modeling each protein tyrosine kinase (PTK) inhibitory activity were selected by genetic algorithm (GA) and multiple linear regression (MLR) approach. The 2D autocorrelation space brings different descriptors for each PTK inhibition and suggests the atomic properties relevant for the inhibitors to interact with each PTK active site. CoMFA and CoMSIA were developed with a focus on interpretative ability using coefficient contour maps. CoMSIA produced significantly better results for all correlations. The results indicate a strong correlation between the inhibitory activity of the modeled compounds and the hydrophobic and H-bond donor fields around them. © 2007 Elsevier Ltd. All rights reserved.

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Título según WOS: 2D Autocorrelation, CoMFA, and CoMSIA modeling of protein tyrosine kinases' inhibition by substituted pyrido[2,3-d]pyrimidine derivatives
Título según SCOPUS: 2D Autocorrelation, CoMFA, and CoMSIA modeling of protein tyrosine kinases' inhibition by substituted pyrido[2,3-d]pyrimidine derivatives
Título de la Revista: BIOORGANIC & MEDICINAL CHEMISTRY
Volumen: 16
Número: 2
Editorial: PERGAMON-ELSEVIER SCIENCE LTD
Fecha de publicación: 2008
Página de inicio: 810
Página final: 821
Idioma: English
URL: http://linkinghub.elsevier.com/retrieve/pii/S0968089607008905
DOI:

10.1016/j.bmc.2007.10.024

Notas: ISI, SCOPUS