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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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Mutations in the QRDR of gyrA gene of M. tuberculosis clinical isolates. The mutated codons and the corresponding amino acids changes are shown at the bottom. The original sequence is shown in the box. Numbers indicate the number of isolates showing the mutations, while the percentage denote the frequencies of occurrence of mutations at the particular codon [11].
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Figure 2: Mutations in the QRDR of gyrA gene of M. tuberculosis clinical isolates. The mutated codons and the corresponding amino acids changes are shown at the bottom. The original sequence is shown in the box. Numbers indicate the number of isolates showing the mutations, while the percentage denote the frequencies of occurrence of mutations at the particular codon [11].

Mentions: Mutations present in the above strains (Figure 2) were identified by sequencing PCR amplified product of gyrA using automated sequencer ABI Prism model 377 version 10.0 with Big dye terminator. The data obtained were compared with the sequence available at the Sanger Center and NCBI using BLAST program [13] and the mutational pattern was compared with the phenotypic susceptibility pattern [14].


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)

Mutations in the QRDR of gyrA gene of M. tuberculosis clinical isolates. The mutated codons and the corresponding amino acids changes are shown at the bottom. The original sequence is shown in the box. Numbers indicate the number of isolates showing the mutations, while the percentage denote the frequencies of occurrence of mutations at the particular codon [11].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Mutations in the QRDR of gyrA gene of M. tuberculosis clinical isolates. The mutated codons and the corresponding amino acids changes are shown at the bottom. The original sequence is shown in the box. Numbers indicate the number of isolates showing the mutations, while the percentage denote the frequencies of occurrence of mutations at the particular codon [11].
Mentions: Mutations present in the above strains (Figure 2) were identified by sequencing PCR amplified product of gyrA using automated sequencer ABI Prism model 377 version 10.0 with Big dye terminator. The data obtained were compared with the sequence available at the Sanger Center and NCBI using BLAST program [13] and the mutational pattern was compared with the phenotypic susceptibility pattern [14].

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