Pharmacophore Modelling, 3D-QSAR Study and Docking of Naphthol derivatives as B-Raf(V600E) Receptor Antagonists

Abstract

ABSTRACT

 B-Raf ^(V600E) is a member of RAF kinase family involved in the ERK/MAP kinase pathway which regulates cellular proliferation, differentiation and survival. A single point mutation of Glutamic acid at position 600 can turn BRAF into an oncoprotein. Three dimensional QSAR (quantitative structure–activity relationship) and molecular docking approaches were performed on naphthol derivatives to understand their structural requisites and binding mode of the best fitted ligand for B-Raf inhibitory activity. Five featured pharmacophore ADDRR.43 was considered to be the best hypothesis which yielded a statistically significant 3D-QSAR model built with 1A^o grid spacing, PLS factor = 2, Regression coefficient (R²) =0.9241, Cross validation coefficient (Q²) = 0.712, Root Mean Square Deviation (RMSD) =0.5065, Pearson-R =0.9468. The Inhibitor 11 is found to be the best fitted ligand for this hypothesis and was subjected to docking study which suggested that the hydrogen bonds, hydrophobic bonds and electrostatic interactions were closely related to B-Raf inhibitory activity and are in compliance with the predicted model. The geometry and features of this pharmacophore model emphasizes important binding features which will be useful for the design of selective B-Raf ^(V600E) antagonists.