Dual-targeted hit identification using pharmacophore screening

• DOI: 10.1007/s10822-019-00245-5
• Publication Date: 2019-11-06T09:03:09Z
• Authors: Galyna P. Volynets; Sergiy A. Starosyla; Mariia Yu. Rybak; Volodymyr G. Bdzhola; Oksana P. Kovalenko; Vasyl S. Vdovin; Sergiy M. Yarmoluk; Michail A. Tukalo
• Keywords: Aminoacylation; IC50

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.