3D QSAR and pharmacophore identification of isoquinoline and benzimidazole analogs as potent C-RAF inhibitors

Blessy Christina N.*, Manoj Kumar Mahto, Uday Kumar Dasari, Matcha Bhaskar

Abstract


The C-Raf inhibitors obstruct the activity of other signaling pathways which are implicated in many tumors. Hence C-RAF inhibition has emerged as a promising therapeutic target for many cancers. A series of 33 novel Isoquinoline and benzimidazole derivatives has been reported as C-RAF inhibitors. A combined study of pharmacophore prediction, atom based 3d QSAR and molecular docking explored the structural insights of these inhibitors. A Five point pharmacophore hypothesis AADHR.  719 yielded a statistically significant 3D QSAR model with PLS factors as r2= 0.93, Q2= 0.51, RMSE=0.177.  Docking study also revealed the binding orientations of active ligand 10e at active site amino acid residue (GLU478, GLN610, PHE443) of C-Raf. The results of ligand based pharmacophore hypothesis and atom based 3D QSAR highlighted the important binding features of novel Isoquinoline and Benzimidazole derivaties as potent C-Raf inhibitors.

Keywords


Pharmacophore; 3D QSAR; Isoquinoline; bezimidazole; C-RAF; Docking

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DOI: http://dx.doi.org/10.21746/ijbio.2013.10.0010

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