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Docking studies on novel analogues of 8 methoxy fluoroquinolones against GyrA mutants of Mycobacterium tuberculosis.

Anand RS, Somasundaram S, Doble M, Paramasivan CN - BMC Struct. Biol. (2011)

Bottom Line: They showed consistently high binding affinity values of -10.3 and -10.1 kcal/mol respectively with the target receptors.Of these, the guanosine ester showed highest binding affinity score and its log P value lied within the Lipinski's range indicating that it could have better absorptivity when it is orally administered thereby having an enhanced activity against MTB.The docking results showed that the addition of the cholesteryl and guanosine esters to the 'DNA gyrase binding' region of gatifloxacin and moxifloxacin enhanced the binding affinity of these parent molecules with the mutant DNA gyrase receptors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biotechnology, Sri Venkateswara College of Engineering, Sriperumbudur, India.

ABSTRACT

Background: Fluoroquinolone resistance is a serious threat in the battle against the treatment of multi drug resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB). Fluoroquinolone resistant isolates from India had shown to have evolved several mutants in the quinolone resistance determining region (QRDR) of DNA gyrase A subunit (GyrA), the target of fluoroquinolone. In view of high prevalence of mutations in the 'hot spot' region, a study on combinatorial drug design was carried out to identify better analogues for the treatment of MDR-TB. The gyrA subunit 'hot spot' region of codons 90, 94 and 95 were modeled into their corresponding protein folds and used as receptors for the docking studies. Further, invitro tests were carried using the parent compounds, namely gatifloxacin and moxifloxacin and correlated with the obtained docking scores.

Results: Molecular docking and in vitro studies correlated well in demonstrating the enhanced activity of moxifloxacin, when compared to gatifloxacin, on ofloxacin sensitive and resistant strains comprising of clinical isolates of MDR-TB. The evolved lead structures targeting against mutant QRDR receptors were guanosine and cholesteryl esters of gatifloxacin and moxifloxacin. They showed consistently high binding affinity values of -10.3 and -10.1 kcal/mol respectively with the target receptors. Of these, the guanosine ester showed highest binding affinity score and its log P value lied within the Lipinski's range indicating that it could have better absorptivity when it is orally administered thereby having an enhanced activity against MTB.

Conclusions: The docking results showed that the addition of the cholesteryl and guanosine esters to the 'DNA gyrase binding' region of gatifloxacin and moxifloxacin enhanced the binding affinity of these parent molecules with the mutant DNA gyrase receptors. Viewing the positive correlation for the docking and in vitro results with the parent compounds, these lead structures could be further evaluated for their in vitro and in vivo activity against MDR-TB.

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Binding of Ligand 36 with the binding site of first mutant receptor. (A) The H- bond interactions are indicated by arrow marking in the colour of the corresponding aminoacid. (B) Shows the orientation of ligand 36 with the hydrophobic surfaces (Red) and hydrophilic surfaces (blue) in the binding pocket of the first mutant receptor.
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Figure 9: Binding of Ligand 36 with the binding site of first mutant receptor. (A) The H- bond interactions are indicated by arrow marking in the colour of the corresponding aminoacid. (B) Shows the orientation of ligand 36 with the hydrophobic surfaces (Red) and hydrophilic surfaces (blue) in the binding pocket of the first mutant receptor.

Mentions: Endogeneous ester modification of gatifloxacin, Ligand 36, which had a cholesteryl ester at this position, yielded a reasonably good docking score (-10.1 kcal/mol) with respect to first, third and wild type receptors (Table 2). This good binding affinity arises from the H bond interaction between the nitrogen atom in the 39th position in the structure and the carbonyl oxygen of Leucine 746. The energy value of this interaction was -2.5 kcal/mol and a bond length of 2.97 nm (Figure 9A). The docked image of ligand 36 in the binding pocket of GyrA showed high hydrophobic surface interactions which could also contribute to the observed high binding affinity (Figure 9B).


Docking studies on novel analogues of 8 methoxy fluoroquinolones against GyrA mutants of Mycobacterium tuberculosis.

Anand RS, Somasundaram S, Doble M, Paramasivan CN - BMC Struct. Biol. (2011)

Binding of Ligand 36 with the binding site of first mutant receptor. (A) The H- bond interactions are indicated by arrow marking in the colour of the corresponding aminoacid. (B) Shows the orientation of ligand 36 with the hydrophobic surfaces (Red) and hydrophilic surfaces (blue) in the binding pocket of the first mutant receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3298726&req=5

Figure 9: Binding of Ligand 36 with the binding site of first mutant receptor. (A) The H- bond interactions are indicated by arrow marking in the colour of the corresponding aminoacid. (B) Shows the orientation of ligand 36 with the hydrophobic surfaces (Red) and hydrophilic surfaces (blue) in the binding pocket of the first mutant receptor.
Mentions: Endogeneous ester modification of gatifloxacin, Ligand 36, which had a cholesteryl ester at this position, yielded a reasonably good docking score (-10.1 kcal/mol) with respect to first, third and wild type receptors (Table 2). This good binding affinity arises from the H bond interaction between the nitrogen atom in the 39th position in the structure and the carbonyl oxygen of Leucine 746. The energy value of this interaction was -2.5 kcal/mol and a bond length of 2.97 nm (Figure 9A). The docked image of ligand 36 in the binding pocket of GyrA showed high hydrophobic surface interactions which could also contribute to the observed high binding affinity (Figure 9B).

Bottom Line: They showed consistently high binding affinity values of -10.3 and -10.1 kcal/mol respectively with the target receptors.Of these, the guanosine ester showed highest binding affinity score and its log P value lied within the Lipinski's range indicating that it could have better absorptivity when it is orally administered thereby having an enhanced activity against MTB.The docking results showed that the addition of the cholesteryl and guanosine esters to the 'DNA gyrase binding' region of gatifloxacin and moxifloxacin enhanced the binding affinity of these parent molecules with the mutant DNA gyrase receptors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biotechnology, Sri Venkateswara College of Engineering, Sriperumbudur, India.

ABSTRACT

Background: Fluoroquinolone resistance is a serious threat in the battle against the treatment of multi drug resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB). Fluoroquinolone resistant isolates from India had shown to have evolved several mutants in the quinolone resistance determining region (QRDR) of DNA gyrase A subunit (GyrA), the target of fluoroquinolone. In view of high prevalence of mutations in the 'hot spot' region, a study on combinatorial drug design was carried out to identify better analogues for the treatment of MDR-TB. The gyrA subunit 'hot spot' region of codons 90, 94 and 95 were modeled into their corresponding protein folds and used as receptors for the docking studies. Further, invitro tests were carried using the parent compounds, namely gatifloxacin and moxifloxacin and correlated with the obtained docking scores.

Results: Molecular docking and in vitro studies correlated well in demonstrating the enhanced activity of moxifloxacin, when compared to gatifloxacin, on ofloxacin sensitive and resistant strains comprising of clinical isolates of MDR-TB. The evolved lead structures targeting against mutant QRDR receptors were guanosine and cholesteryl esters of gatifloxacin and moxifloxacin. They showed consistently high binding affinity values of -10.3 and -10.1 kcal/mol respectively with the target receptors. Of these, the guanosine ester showed highest binding affinity score and its log P value lied within the Lipinski's range indicating that it could have better absorptivity when it is orally administered thereby having an enhanced activity against MTB.

Conclusions: The docking results showed that the addition of the cholesteryl and guanosine esters to the 'DNA gyrase binding' region of gatifloxacin and moxifloxacin enhanced the binding affinity of these parent molecules with the mutant DNA gyrase receptors. Viewing the positive correlation for the docking and in vitro results with the parent compounds, these lead structures could be further evaluated for their in vitro and in vivo activity against MDR-TB.

Show MeSH
Related in: MedlinePlus