Exploring the possible binding mode of trisubstituted benzimidazoles analogues in silico for novel drug designtargeting Mtb FtsZ

Abstract

FtsZ, an essential cytokinesis protein, was a highly promising target for antibacterial agents. Following up the identification of trisubstituted benzimidazoles targeting Mycobacterium tuberculosis FtsZ (Mtb FtsZ) in previous studies and in order to explore the possible binding mode of these analogues, in silico methodologies such as 3D-QSAR, ProFunc analysis, molecular docking and molecular dynamic simulation were performed. They corroborated well with each other and gave credence to the proposed binding mechanism of trisubstituted benzimidazoles in the interdomain cleft region of Mtb FtsZ. The benzimidazole scaffold and cyclohexyl group of trisubstituted benzimidazoles were orthogonal to each other in low energy state and inclosed in a most hydrophobic environment formed by residues from the C-terminal β sheets and H7 helix. The carbamate groups at the 5-position extended outward form the cleft cavity to the hydrophilic surface. The substituents at the 6-position fitted into the top portion of the cleft by directly interacting with the T7 loop. It was believed that the hydrophobic interactions and the polar contacts were major contributors to the stabilization of the ligand binding in the interdomain cleft. The binding mechanism provided useful clues to design new trisubstituted benzimidazoles inhibitors of Mtb FisZ with promising activity. The work presented here may even be expanded tremendously to screen novel Mtb FtsZ inhibitors with different scaffolds by using the molecular dynamic refined Mtb FtsZ structure and docking based 3D QSAR CoMFA.