TY - JOUR
T1 - Dual-targeted hit identification using pharmacophore screening
AU - Volynets, Galyna P.
AU - Starosyla, Sergiy A.
AU - Rybak, Mariia Yu
AU - Bdzhola, Volodymyr G.
AU - Kovalenko, Oksana P.
AU - Vdovin, Vasyl S.
AU - Yarmoluk, Sergiy M.
AU - Tukalo, Michail A.
N1 - Funding Information:
This work was supported by the Science and Technology Center in Ukraine (Contract No. 6258) and by the National Academy of Sciences of Ukraine (Contract No. 80–10/04–2019). Authors are grateful to Dr. Stephen Cusack and Dr. Andres Palencia (EMBL Grenoble Outstation, France) for the gift of plasmid encoding M. tuberculosis LeuRS. We also thank Prof. Vasyl Mel’nyk (National Institute of Phthisiology and Pulmonology named after F.G. Yanovsky of the NAMS of Ukraine, Kyiv, Ukraine) for providing the gene encoding M. tuberculosis MetRS.
Funding Information:
This work was supported by the Science and Technology Center in Ukraine (Contract No. 6258) and by the National Academy of Sciences of Ukraine (Contract No. 80?10/04?2019). Authors are grateful to Dr. Stephen Cusack and Dr. Andres Palencia (EMBL Grenoble Outstation, France) for the gift of plasmid encoding M. tuberculosis LeuRS. We also thank Prof. Vasyl Mel?nyk (National Institute of Phthisiology and Pulmonology named after F.G. Yanovsky of the NAMS of Ukraine, Kyiv, Ukraine) for providing the gene encoding M. tuberculosis MetRS.
Publisher Copyright:
© 2019, Springer Nature Switzerland AG.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
KW - Dual-targeted inhibitor
KW - Leucyl-tRNA synthetase
KW - Methionyl-tRNA synthetase
KW - Molecular docking
KW - Mycobacterium tuberculosis
KW - Pharmacophore modeling
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U2 - 10.1007/s10822-019-00245-5
DO - 10.1007/s10822-019-00245-5
M3 - Article
C2 - 31691918
AN - SCOPUS:85074831180
SN - 0920-654X
VL - 33
SP - 955
EP - 964
JO - Journal of Computer-Aided Molecular Design
JF - Journal of Computer-Aided Molecular Design
IS - 11
ER -