title: Structural investigation of PAP derivatives by CoMFA and CoMSIA reveals novel insight towards inhibition of Bcr-Abl oncoprotein.
abstract: Molecular modeling by 3D-QSAR comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were employed on a series of phenylaminopyrimidine-based (PAP) Bcr-Abl inhibitors. The chemical structures of 63 PAP analogues were aligned using a template extracted from the crystal structure of STI571 bound to Abl kinase. Subsequently, the structures built were divided into training and test sets that include 53 and 10 compounds, respectively. Statistical results showed that the 3D-QSAR models generated from CoMSIA were superior to CoMFA (CoMSIA; q2=0.66, r2=0.94, N=3, F=139.09, r2pred=0.64 while CoMFA; q2=0.53, r2=0.73, N=3, F=43.53, r2pred=0.61). Based on the contour interpretation, the attachment of hydrophobic and bulky groups to the phenyl and pyrrolidine (D- and E-ring of NS-187, respectively) along with highly electronegative groups around the D-ring are important structural features for the design of second-generation Bcr-Abl inhibitors. The generated models are predictive based on reproducible values of the predicted compared with experimental activities in the test set. Further, the complementary analysis of contour maps to the Bcr-Abl binding site suggested the anchor points for binding affinity.
authors: Life Science Division, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650, South Korea. amor.san_juan@up.edu.ph
authors: Amor A
authors: AA
authors: San Juan
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D011743:Pyrimidines; D016044:Fusion Proteins, bcr-abl