Discovery of New Inhibitors of Mycobacterium tuberculosis InhA Enzyme Using Virtual Screening and a 3D-Pharmacophore-Based Approach

Abstract

Mycobacterium tuberculosis InhA (MtInhA) is an attractive enzyme to drug discovery efforts due to its validation as an effective biological target for tuberculosis therapy. In this work, two different virtual-ligand-screening approaches were applied in order to identify new InhA inhibitors' candidates from a library of ligands selected from the ZINC database. First, a 3-D pharmacophore model was built based on 36 available MtInhA crystal structures. By combining structure-based and ligand-based information, four pharmacophoric points were designed to select molecules able to satisfy the binding features of MtInhA substrate-binding cavity. The second approach consisted of using four well established docking programs, with different search algorithms, to compare the binding mode and score of the selected molecules from the aforementioned library. After detailed analyses of the results, six ligands were selected for in vitro analysis. Three of these molecules presented a satisfactory inhibitory activity with IC50 values ranging from 24 (±2) μM to 83 (±5) μM. The best compound presented an uncompetitive inhibition mode to NADH and 2-trans-dodecenoyl-CoA substrates, with Ki values of 24 (±3) μM and 20 (±2) μM, respectively. These molecules were not yet described as antituberculars or as InhA inhibitors, making its novelty interesting to start efforts on ligand optimization in order to identify new effective drugs against tuberculosis having InhA as a target. More studies are underway to dissect the discovered uncompetitive inhibitor interactions with MtInhA.

Piperazine derivatives: Synthesis, inhibition of the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase and SAR studies

“…These mycolic acids have been associated with M. tuberculosis virulence [9], the ability of M. tuberculosis to survive and replicate inside M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 6 interactions involving a ribose hydroxyl, the Tyr158 hydroxyl and a hydrogen bond acceptor in the compounds. Consistent with our strategy [22], this substrate-proteinligand interaction has been observed as a pharmacophoric point in virtual screening campaigns for novel MtInhA inhibitors. However, the structural and electronic requirements for these hydrogen bond donor-acceptor pairs have not been extensively examined.…”

Molecular Docking and Structure-Based Drug Design Strategies

“…In a recent study, a series of novel InhA inhibitors was identified through a virtual screening strategy. The authors employed a multistage approach, integrating pharmacophore modeling and molecular docking [207]. First, a four-point 3D pharmacophore model was generated by superimposing 36 InhA crystallographic structures available in the PDB.…”

Virtual Screening Strategies: A State of Art to Combat with Multiple Drug Resistance Strains

“…Two different virtual-screening approaches were applied in order to identify novel inhibitors for the Mycobacterium tuberculosis InhA (MtInhA) target [73]. First, a 3-D pharmacophore model was built based on 36 available MtInhA crystal structures.…”