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Hybrid phenylthiazole and 1,3,5-triazine target cytosolic leucyl-tRNA synthetase for antifungal action as revealed by molecular docking studies.

Singh UP, Bhat HR, Gahtori P, Singh RK - In Silico Pharmacol (2013)

Bottom Line: This process is very crucial for survival of micro-organism and thus the inhibition of LeuRS offered a novel and lucrative target for developing new antimicrobials.Docking studies using hybrid phenylthiazole-1,3,5-triazine derivatives revealed that these molecules acted as probable inhibitors of candida albicans cytosolic leucyl-tRNA synthetase.The conjugates of phenylthiazole and 1,3,5-triazine can act as lead molecules towards the development of potential leucyl-tRNA synthetase inhibitors on the basis of molecular docking runs, which contribute to the possible mechanism of antifungal activity of these analogues.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, Sam Higginbottom Institute of Agriculture, Technology & Sciences, Deemed University, Allahabad, 211007 India ; Nucleic Acids Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad, 211002 India ; Archimedes DoRa5 Visiting Fellow, Institute of Chemistry, Division of Bio-organic Chemistry, Institute of Chemistry, University of Tartu, Tartu, Estonia.

ABSTRACT

Background: Leucyl-tRNA synthetase (LeuRS) is one of the essential enzymes belonging to the family of aminoacyl-tRNA synthetases (aaRSs), which executes the translation of genetic code by catalyzing the specific attachment of amino acids to their cognate tRNAs. This process is very crucial for survival of micro-organism and thus the inhibition of LeuRS offered a novel and lucrative target for developing new antimicrobials.

Findings: Docking studies using hybrid phenylthiazole-1,3,5-triazine derivatives revealed that these molecules acted as probable inhibitors of candida albicans cytosolic leucyl-tRNA synthetase.

Conclusion: The conjugates of phenylthiazole and 1,3,5-triazine can act as lead molecules towards the development of potential leucyl-tRNA synthetase inhibitors on the basis of molecular docking runs, which contribute to the possible mechanism of antifungal activity of these analogues.

No MeSH data available.


Docked pose of compounds 1-8 in Leu-tRNA synthetase.
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Fig2: Docked pose of compounds 1-8 in Leu-tRNA synthetase.

Mentions: Till date a very few leucyl-tRNA synthetase inhibitors have been reported as antifungal agents. One such molecule AN2690, a benzoxaborole derivative as potent non-competitive inhibitor is under development. In the present study, molecular docking studies of hybrid phenylthiazole-1,3,5-triazine derivatives have been carried onto the binding site of candida albicans cytosolic leucyl-tRNA synthetase editing domain to exemplify the orientation & binding affinity, and Dockscores calculated from the docked conformations of the thymidylate synthetase -inhibitor complexes using LigandFit within DS 2.5. Docking results were discussed on the parameters such as hydrogen bond, pi-pi(hydrophobic) and non-polar pi-cation (non-covalent) interactions. According to Gallivan and Dougherty, pi-cation interaction energies are considered of the same order of magnitude as hydrogen bonds or salt bridges and play an important role in molecular recognition and interaction with ligands. These interactions of the title compounds have been discussed, if the interatomic distance fell below 6 Å (Gallivan and Dougherty 1999). Considering the magnitude of interacting forces for receptor-ligand interaction, the entire set of molecules were rigorously docked onto the active site of thymidylate synthetase, using the same protocol and analyzed through above mentioned parameters and results presented in Figure 2 (compounds 1-8) and Figure 3 (compounds 9-15), Tables 1 and 2.Figure 2


Hybrid phenylthiazole and 1,3,5-triazine target cytosolic leucyl-tRNA synthetase for antifungal action as revealed by molecular docking studies.

Singh UP, Bhat HR, Gahtori P, Singh RK - In Silico Pharmacol (2013)

Docked pose of compounds 1-8 in Leu-tRNA synthetase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230311&req=5

Fig2: Docked pose of compounds 1-8 in Leu-tRNA synthetase.
Mentions: Till date a very few leucyl-tRNA synthetase inhibitors have been reported as antifungal agents. One such molecule AN2690, a benzoxaborole derivative as potent non-competitive inhibitor is under development. In the present study, molecular docking studies of hybrid phenylthiazole-1,3,5-triazine derivatives have been carried onto the binding site of candida albicans cytosolic leucyl-tRNA synthetase editing domain to exemplify the orientation & binding affinity, and Dockscores calculated from the docked conformations of the thymidylate synthetase -inhibitor complexes using LigandFit within DS 2.5. Docking results were discussed on the parameters such as hydrogen bond, pi-pi(hydrophobic) and non-polar pi-cation (non-covalent) interactions. According to Gallivan and Dougherty, pi-cation interaction energies are considered of the same order of magnitude as hydrogen bonds or salt bridges and play an important role in molecular recognition and interaction with ligands. These interactions of the title compounds have been discussed, if the interatomic distance fell below 6 Å (Gallivan and Dougherty 1999). Considering the magnitude of interacting forces for receptor-ligand interaction, the entire set of molecules were rigorously docked onto the active site of thymidylate synthetase, using the same protocol and analyzed through above mentioned parameters and results presented in Figure 2 (compounds 1-8) and Figure 3 (compounds 9-15), Tables 1 and 2.Figure 2

Bottom Line: This process is very crucial for survival of micro-organism and thus the inhibition of LeuRS offered a novel and lucrative target for developing new antimicrobials.Docking studies using hybrid phenylthiazole-1,3,5-triazine derivatives revealed that these molecules acted as probable inhibitors of candida albicans cytosolic leucyl-tRNA synthetase.The conjugates of phenylthiazole and 1,3,5-triazine can act as lead molecules towards the development of potential leucyl-tRNA synthetase inhibitors on the basis of molecular docking runs, which contribute to the possible mechanism of antifungal activity of these analogues.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, Sam Higginbottom Institute of Agriculture, Technology & Sciences, Deemed University, Allahabad, 211007 India ; Nucleic Acids Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad, 211002 India ; Archimedes DoRa5 Visiting Fellow, Institute of Chemistry, Division of Bio-organic Chemistry, Institute of Chemistry, University of Tartu, Tartu, Estonia.

ABSTRACT

Background: Leucyl-tRNA synthetase (LeuRS) is one of the essential enzymes belonging to the family of aminoacyl-tRNA synthetases (aaRSs), which executes the translation of genetic code by catalyzing the specific attachment of amino acids to their cognate tRNAs. This process is very crucial for survival of micro-organism and thus the inhibition of LeuRS offered a novel and lucrative target for developing new antimicrobials.

Findings: Docking studies using hybrid phenylthiazole-1,3,5-triazine derivatives revealed that these molecules acted as probable inhibitors of candida albicans cytosolic leucyl-tRNA synthetase.

Conclusion: The conjugates of phenylthiazole and 1,3,5-triazine can act as lead molecules towards the development of potential leucyl-tRNA synthetase inhibitors on the basis of molecular docking runs, which contribute to the possible mechanism of antifungal activity of these analogues.

No MeSH data available.