Abstract

In Mycobacterium tuberculosis, shikimate pathway is essential for amino acid biosynthesis, siderophores formation to overcome starvation, to survive in low oxygen conditions as well as for pathogen’s virulence and growth. 3-Dehydroquinate synthase of M. tuberculosis plays a vital role in the biosynthesis of aromatic amino acids and various secondary metabolites through shikimate pathway and is responsible for development of drug resistance. Thus, designing inhibitors towards this attractive drug target 3-dehydroquinate synthase to inhibit the synthesis of aromatic amino acids and essential secondary metabolites could prevent survival of this pathogen. In the present work, docking studies were performed using the 3-dehydroquinate synthase crystal structure against 1082 approved DrugBank compounds. The best DrugBank compound and substrate analogue (carbaphosphonate) were subjected to shape screening against 21 million compounds and resulted compounds constituted the AroB ligand-dataset. The library was subjected to rigid receptor docking, quantum polarized ligand docking, and induced fit docking followed by molecular mechanics-generalized born and surface area calculations resulted in two compounds possess the best scoring functions (XP GScore). Molecular dynamics simulations (50 ns) in the solvated model system determined consistency nature of AroB-lead 1 over the AroB-carbaphosphonate complex. Moreover, upon comparison of the proposed leads with the best DrugBank compound and carbaphosphonate, the leads showed favorable absorption, distribution, metabolism, excretion and toxicity properties within the range of 95 % FDA approved drugs, and showing better antagonist properties than the existing inhibitors. Hence these leads were proposed as novel inhibitors against tuberculosis.