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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.


Role of aminoacyl-tRNA synthetase (aaRS) enzyme in translating the genetic code by catalyzing the specific attachment of amino acids to their cognate tRNAs.
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Fig1: Role of aminoacyl-tRNA synthetase (aaRS) enzyme in translating the genetic code by catalyzing the specific attachment of amino acids to their cognate tRNAs.

Mentions: Aminoacyl-tRNA synthetase (aaRS) enzymes have recently gained focus of attention as novel potential target for antimicrobial drug research (Pohlmann and Brötz-Oesterhelt, 2004). They perform a crucial role in translating the genetic code by catalyzing the specific attachment of amino acids to their cognate tRNAs in a two step reaction: activation of amino acid with ATP to form enzyme-bound aminoacyl-AMP (with release of pyrophosphate), and transfer of amino acid moiety to cognate tRNA, releasing AMP and charged tRNA (Figure 1). Based on the architecture of their catalytic domains, aaRSs belong to two distinct classes. Class I enzymes contain a typical Rossman fold in the active site, with the HIGH and KMSKS motifs that stabilize the transition state of the reaction for amino acid activation using ATP-binding energy. Class II enzymes harbor an antiparallel β-sheet domain that provides a rigid template for amino acid and ATP binding, with three characteristic motifs required for dimerization and substrate binding (Hurdle et al. 2005). A newly discovered antifungal agent AN2690, (under clinical investigation) reported to act by inactivating fungal LeuRS, a class I aaRS enzyme is responsible for charging leucine to its cognate tRNA correctly (Kim et al. 2003). As a result, design and discovery of LeuRS inhibitors surfaces as a prolific approach to attenuate microorganism growth for exploring novel antifungal agents via arrest of fungal protein synthesis (Hendrickson et al. Hendrickson and Schimmel 2003; Rock et al., 2007).Figure 1


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)

Role of aminoacyl-tRNA synthetase (aaRS) enzyme in translating the genetic code by catalyzing the specific attachment of amino acids to their cognate tRNAs.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Role of aminoacyl-tRNA synthetase (aaRS) enzyme in translating the genetic code by catalyzing the specific attachment of amino acids to their cognate tRNAs.
Mentions: Aminoacyl-tRNA synthetase (aaRS) enzymes have recently gained focus of attention as novel potential target for antimicrobial drug research (Pohlmann and Brötz-Oesterhelt, 2004). They perform a crucial role in translating the genetic code by catalyzing the specific attachment of amino acids to their cognate tRNAs in a two step reaction: activation of amino acid with ATP to form enzyme-bound aminoacyl-AMP (with release of pyrophosphate), and transfer of amino acid moiety to cognate tRNA, releasing AMP and charged tRNA (Figure 1). Based on the architecture of their catalytic domains, aaRSs belong to two distinct classes. Class I enzymes contain a typical Rossman fold in the active site, with the HIGH and KMSKS motifs that stabilize the transition state of the reaction for amino acid activation using ATP-binding energy. Class II enzymes harbor an antiparallel β-sheet domain that provides a rigid template for amino acid and ATP binding, with three characteristic motifs required for dimerization and substrate binding (Hurdle et al. 2005). A newly discovered antifungal agent AN2690, (under clinical investigation) reported to act by inactivating fungal LeuRS, a class I aaRS enzyme is responsible for charging leucine to its cognate tRNA correctly (Kim et al. 2003). As a result, design and discovery of LeuRS inhibitors surfaces as a prolific approach to attenuate microorganism growth for exploring novel antifungal agents via arrest of fungal protein synthesis (Hendrickson et al. Hendrickson and Schimmel 2003; Rock et al., 2007).Figure 1

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.