Discovery of New Inhibitors of Enoyl-ACP Reductase via Structure-Based Virtual Screening

A virtual screening protocol, by combining on 3D-QSAR model with molecular docking procedure and prediction of physico-chemical properties, was applied to find novel inhibitors of Enoyl ACP reductase against M. tuberculosis. Initially, a series of thirty two isoniazid analogues was collected from literature and was investigated against tuberculosis target (PDB Id: 2IE0) using molecular docking. The docking studies were used to position the inhibitors into the active site of Enoly ACP reductase to derive a receptor based 3D-QSAR model. 3D-QSAR model was built and showed to be statistically significant and with a high predictive ability for the training (R2= 0.97) and test set (Q2= 0.73). Contour cubes analysis of the 3D-QSAR model revealed the chemical features necessary for the enoyl ACP reductase enzyme inhibition. The model was then used for virtual screening with the aim of identifying new inhibitors of Enoyl ACP reductase and predicts their potential activity. The outcome of the above studies, ten new molecules are proposed as Enoyl ACP reductase inhibitors with high binding affinity, activity prediction and favorable ADME properties.