title: 2D Autocorrelation, CoMFA, and CoMSIA modeling of protein tyrosine kinases' inhibition by substituted pyrido[2,3-d]pyrimidine derivatives.
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.
authors.affiliation: Centro de Bioinformática y Simulación Molecular, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, Chile. jcaballero@utalca.cl
authors.forename: Julio
authors.initials: J
authors.lastname: Caballero
authors.forename: Michael
authors.initials: M
authors.lastname: Fernández
authors.forename: Mario
authors.initials: M
authors.lastname: Saavedra
authors.forename: Fernando D
authors.initials: FD
authors.lastname: González-Nilo
mesh_terms: D000465:Algorithms; D015195:Drug Design; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D021281:Quantitative Structure-Activity Relationship; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D019061:src-Family Kinases