2/3D-QSAR, molecular docking and MD simulation studies of FtsZ protein targeting benzimidazoles derivatives

The development of multi-drug and extensively-drug resistant strains of Mycobacterium tuberculosis (Mtb) have encouraged to develop new anti-TB agents with a unique mechanism of action. FtsZ, an essential protein of bacterial cytokinesis, has emerged as a validated target for antibacterial therapy. This study describes the utility of benzimidazoles (BI) derivatives as potential FtsZ inhibitors. Through 2/3D QSAR (MLR) molecular modeling, new BI-inhibitors with improved activity have been designed. Statistically significant models from 2D-QSAR (r² = 0.90, q² = 85 and pred_r² = 0.60) indicated that the descriptors such as SaaOcount, -ve Potential Surface Area, and SdsCHE-index modulate the activity of a molecule. Similarly, 3D-QSAR (r² = 0.78, q² = 0.69 and pred_r² = 0.59) results indicated both electrostatic and steric descriptors play a pivotal role. These indications prompted us to design 223 new BI-derivatives, out of which three BI-derivatives (D-83, D-116 and D-223) have shown some promising results.