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Dual-targeted hit identification using pharmacophore screening.
- Source :
-
Journal of Computer-Aided Molecular Design . Nov2019, Vol. 33 Issue 11, p955-964. 10p. - Publication Year :
- 2019
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 0920654X
- Volume :
- 33
- Issue :
- 11
- Database :
- Academic Search Index
- Journal :
- Journal of Computer-Aided Molecular Design
- Publication Type :
- Academic Journal
- Accession number :
- 140064910
- Full Text :
- https://doi.org/10.1007/s10822-019-00245-5