Screening of a Novel Fragment Library with Functional Complexity against Mycobacterium tuberculosis InhA

ChemMedChem. 2018 Apr 6;13(7):672-677. doi: 10.1002/cmdc.201700774. Epub 2018 Feb 19.

Abstract

Our findings reported herein provide support for the benefits of including functional group complexity (FGC) within fragments when screening against protein targets such as Mycobacterium tuberculosis InhA. We show that InhA fragment actives with FGC maintained their binding pose during elaboration. Furthermore, weak fragment hits with functional group handles also allowed for facile fragment elaboration to afford novel and potent InhA inhibitors with good ligand efficiency metrics for optimization.

Keywords: InhA; fragment based drug discovery; functional group complexity; tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry*
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / chemistry
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Mycobacterium tuberculosis / enzymology*
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases / chemistry
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry*
  • Surface Plasmon Resonance

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Enzyme Inhibitors
  • Ligands
  • Small Molecule Libraries
  • Oxidoreductases
  • InhA protein, Mycobacterium