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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 35 with the binding site in the third mutant receptor. The H- bond interactions are indicated by arrow marking in the colour of the corresponding amino acid.
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Figure 8: Binding of Ligand 35 with the binding site in the third mutant receptor. The H- bond interactions are indicated by arrow marking in the colour of the corresponding amino acid.

Mentions: The modifications to the 'DNA gyrase binding' region mainly consisted of esters at the carboxyl site. The modifications at this site yielded docking scores ranging from -7.7 (Ligand 38) to 10.4 (Ligand 35). With respect to the nucleoside esters, Ligand 35, the guanosine ester of moxifloxacin, showed the highest binding score namely, -10.3 kcal/mol for first, second, third and wild type receptors. Whereas for the fourth mutant receptor it showed an enhanced score of -10.4. The increased affinity of this ligand when compared to the other nucleoside esters can be correlated to the four hydrogen bond interactions it formed with Serine 747, valine 690, Leucine 689 and arginine 658 (Figure 8). The strongest interaction was found between the ester oxygen and hydroxyl group of serine 747 with a H-bond energy of -2.5 kcal/mol and a bond length of 2.83 nm. The net interactions yielded a binding affinity of -10.3 kcal/mol for this compound with this receptor (Table 2).


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 35 with the binding site in the third mutant receptor. 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 8: Binding of Ligand 35 with the binding site in the third mutant receptor. The H- bond interactions are indicated by arrow marking in the colour of the corresponding amino acid.
Mentions: The modifications to the 'DNA gyrase binding' region mainly consisted of esters at the carboxyl site. The modifications at this site yielded docking scores ranging from -7.7 (Ligand 38) to 10.4 (Ligand 35). With respect to the nucleoside esters, Ligand 35, the guanosine ester of moxifloxacin, showed the highest binding score namely, -10.3 kcal/mol for first, second, third and wild type receptors. Whereas for the fourth mutant receptor it showed an enhanced score of -10.4. The increased affinity of this ligand when compared to the other nucleoside esters can be correlated to the four hydrogen bond interactions it formed with Serine 747, valine 690, Leucine 689 and arginine 658 (Figure 8). The strongest interaction was found between the ester oxygen and hydroxyl group of serine 747 with a H-bond energy of -2.5 kcal/mol and a bond length of 2.83 nm. The net interactions yielded a binding affinity of -10.3 kcal/mol for this compound with this receptor (Table 2).

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