Dual-targeted hit identification using pharmacophore screening
| Autor: | Volodymyr G. Bdzhola, Galyna P. Volynets, Sergiy A. Starosyla, O. P. Kovalenko, V. S. Vdovin, Michail A. Tukalo, Mariia Yu Rybak, Sergiy M. Yarmoluk |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Molecular model Antitubercular Agents Aminoacylation Computational biology Methionine-tRNA Ligase 01 natural sciences Mycobacterium tuberculosis 0103 physical sciences Drug Discovery Humans Tuberculosis Physical and Theoretical Chemistry Enzyme Inhibitors chemistry.chemical_classification 010304 chemical physics biology Drug discovery Leucyl-tRNA synthetase Ligand (biochemistry) biology.organism_classification 0104 chemical sciences Computer Science Applications 010404 medicinal & biomolecular chemistry Enzyme chemistry Leucine-tRNA Ligase Pharmacophore |
| Zdroj: | Journal of computer-aided molecular design. 33(11) |
| ISSN: | 1573-4951 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
| Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |