Identifying the Structural Features of Diphenyl Ether Analogues for InhA Inhibition: A 2D and 3D QSAR Based Study

Background: Enoyl acyl carrier protein reductase (InhA) is a validated target for Mycobacterium. It is an enzyme which is associated with the biosynthesis of mycolic acids in type II fatty acid synthase system. Mycobacterial cell wall majorly comprises mycolic acids, which are responsible for virulence of the microorganism. Several diphenyl ether derivatives have been known to be direct inhibitors of InhA. Objective: In the present work, a Quantitative Structure Activity Relationship (QSAR) study was performed to identify the structural features of diphenyl ether analogues which contribute to InhA inhibitory activity in a favourable way. Methods: Both 2D and 3D QSAR models were built and compared. Several fingerprint based 2D QSAR models were generated and their relationship with the structural features was studied. Models which corroborated the inhibitory activity of the molecules with their structural features were selected and studied in detail. Results: A 2D-QSAR model, with dendritic fingerprints having regression coefficient, for test set molecules Q(2)=0.8132 and for the training set molecules, R-2=0.9607 was obtained. Additionally, an atom-based 3D-QSAR model with Q(2)=0.7697 and R-2=0.9159 was also constructed. Conclusion: The data reported by various models provides guidance for the designing of structurally new diphenyl ether inhibitors with potential activity against InhA of M. tuberculosis.