Dual-targeted hit identification using pharmacophore screening

Galyna P. Volynets, Sergiy A. Starosyla, Mariia Yu Rybak, Volodymyr G. Bdzhola, Oksana P. Kovalenko, Vasyl S. Vdovin, Sergiy M. Yarmoluk, Michail A. Tukalo

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Mycobacterium tuberculosis infection remains a major cause of global morbidity and mortality due to the increase of antibiotics resistance. Dual/multi-target drug discovery is a promising approach to overcome bacterial resistance. In this study, we built ligand-based pharmacophore models and performed pharmacophore screening in order to identify hit compounds targeting simultaneously two enzymes—M. tuberculosis leucyl-tRNA synthetase (LeuRS) and methionyl-tRNA synthetase (MetRS). In vitro aminoacylation assay revealed five compounds from different chemical classes inhibiting both enzymes. Among them the most active compound—3-(3-chloro-4-methoxy-phenyl)-5-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-3H-[1,2,3]triazol-4-ylamine (1) inhibits mycobacterial LeuRS and MetRS with IC50 values of 13 µM and 13.8 µM, respectively. Molecular modeling study indicated that compound 1 has similar binding mode with the active sites of both aminoacyl-tRNA synthetases and can be valuable compound for further chemical optimization in order to find promising antituberculosis agents.

Original languageEnglish (US)
Pages (from-to)955-964
Number of pages10
JournalJournal of Computer-Aided Molecular Design
Issue number11
StatePublished - Nov 1 2019
Externally publishedYes


  • Dual-targeted inhibitor
  • Leucyl-tRNA synthetase
  • Methionyl-tRNA synthetase
  • Molecular docking
  • Mycobacterium tuberculosis
  • Pharmacophore modeling

ASJC Scopus subject areas

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry


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