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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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Interactions of Gatifloxacin with the second and third mutant receptor. The dotted light blue line shows the H-bond interactions of gatifloxacin with third (A) and second mutant receptors (B). The H- bond interactions are indicated by arrow marking in the colour of the corresponding amino acid.
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Figure 5: Interactions of Gatifloxacin with the second and third mutant receptor. The dotted light blue line shows the H-bond interactions of gatifloxacin with third (A) and second mutant receptors (B). The H- bond interactions are indicated by arrow marking in the colour of the corresponding amino acid.

Mentions: The interaction of MFX and GFX with the GyrA binding site showed that they interacted with different amino acid residues at the active site (Figure 4). Only a single H-bonding between the carboxyl oxygen and the hydroxyl group of serine747 existed for moxifloxacin whereas gatifoxacin showed two potential H-bond interactions with asparagine 856 and tyrosine 564. But considering the high binding affinity value of moxifloxacin (-7.9 kcal/mol) when compared to that of gatifloxacin (-7.4 kcal/mol), as observed by Kitchen et al., [26] it could be attributed to other bonding forces. The interaction of gatifloxacin with the second and third mutant GyrA binding site showed that with both the receptors, the H-bond interactions occurs with the Tyrosine 564 and Asparagine 856. The H-bond energy between the carboxyl group of gatifloxacin and the oxygen atom of tyrosine yielded the -2.5 kcal/mol for the third mutant receptor whereas it showed lower value of -1.411 kcal/mol for the second mutant receptor in the presence of non interacting phenylalanine 588. This may explain the net lower affinity value of the second mutant receptor (-7.3 kcal/mol) with respect to the third mutant receptor (-7.4 kcal/mol) (Figure 5).


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)

Interactions of Gatifloxacin with the second and third mutant receptor. The dotted light blue line shows the H-bond interactions of gatifloxacin with third (A) and second mutant receptors (B). The H- bond interactions are indicated by arrow marking in the colour of the corresponding amino acid.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Interactions of Gatifloxacin with the second and third mutant receptor. The dotted light blue line shows the H-bond interactions of gatifloxacin with third (A) and second mutant receptors (B). The H- bond interactions are indicated by arrow marking in the colour of the corresponding amino acid.
Mentions: The interaction of MFX and GFX with the GyrA binding site showed that they interacted with different amino acid residues at the active site (Figure 4). Only a single H-bonding between the carboxyl oxygen and the hydroxyl group of serine747 existed for moxifloxacin whereas gatifoxacin showed two potential H-bond interactions with asparagine 856 and tyrosine 564. But considering the high binding affinity value of moxifloxacin (-7.9 kcal/mol) when compared to that of gatifloxacin (-7.4 kcal/mol), as observed by Kitchen et al., [26] it could be attributed to other bonding forces. The interaction of gatifloxacin with the second and third mutant GyrA binding site showed that with both the receptors, the H-bond interactions occurs with the Tyrosine 564 and Asparagine 856. The H-bond energy between the carboxyl group of gatifloxacin and the oxygen atom of tyrosine yielded the -2.5 kcal/mol for the third mutant receptor whereas it showed lower value of -1.411 kcal/mol for the second mutant receptor in the presence of non interacting phenylalanine 588. This may explain the net lower affinity value of the second mutant receptor (-7.3 kcal/mol) with respect to the third mutant receptor (-7.4 kcal/mol) (Figure 5).

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