Searching for Potential Novel BCR-ABL Tyrosine Kinase Inhibitors Through G-QSAR and Docking Studies of Some Novel 2-Phenazinamine Derivatives.

Abstract

The computational studies on 2-phenazinamines with their protein targets have been carried out to design compounds with potential anticancer activity and selectivity over specific BCR-ABL Tyrosine kinase. This has been achieved through G-QSAR and molecular docking studies. Computational chemistry was done by using VLife MDS 4.3 and Autodock 4.2. 2D and structures of ligands were drawn by using Chemdraw 2D Ultra 8.0 and were converted into 3D. These were optimized by using semi-empirical method called MOPAC. The protein structure was downloaded as PDB file from RCSC protein data bank. PYMOL was used for studying the binding interactions. The G-QSAR models generated were found to possess training (r2=0.8074), cross-validation (q2=0.6521), and external validation (pred_r2=0.5892) which proved their statistical significance. Accordingly, the newly designed series of 2-phenazinamines viz., 3-chloro-4-aryl-1-(phenazin-7-yl) azetidin-2-ones (4a-4e) were subjected to wet lab synthesis. Alternatively, docking studies were also conducted which showed binding interactions of some derivatives with > 30% higher binding energy values than the standard anticancer drug imatinib. The lower energy values obtained for these derivatives indicate energetically favorable interaction with protein binding site as compared to standard imatinib. G-QSAR and molecular docking studies predicted better anticancer activity for the synthesized azitidine derivatives of 2-phenazinamines (4a-4e) as compared to standard drug. It is therefore surmised that the molecular manipulations at appropriate sites of these derivatives suggested by structure activity relationship data will prove to be beneficial in raising anticancer potential.