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Virtual screening of AmpC/β-lactamase as target for antimicrobial resistance in Pseudomonas aeruginosa.

Farmer R, Gautam B, Singh S, Yadav PK, Jain PA - Bioinformation (2010)

Bottom Line: Thus from the entire 1364 NCI diversity set II compounds which were Docked, the best four docking solutions were selected (ZINC12670903, ZINC17465965, ZINC11681166 and ZINC13099024).Further the Complexes were analyzed through LIGPLOT for their interaction for the 4 best docked NCI diversity set II compounds.Thus from the Complex scoring and binding ability it is deciphered that these NCI diversity set II compounds could be promising inhibitors for Pseudomonas aeruginosa using AmpC /β - lactamase as Drug target yet pharmacological studies have to confirm it.

View Article: PubMed Central - PubMed

Affiliation: Department of Computational Biology and Bioinformatics, Sam Higginbottom Institute of Agricultural, Technology and Sciences, Allahabad 211007, U.P, India.

ABSTRACT
AmpC is a group I, class C -lactamase present in most Enterobacteriaceae and in Pseudomonas aeruginosa and other nonfermenting gram-negative bacilli. The β-lactam class of antibiotics is one of the most important structural classes of antibacterial compounds and act by inhibiting the bacterial D ,D - transpeptidases that are responsible for the final step of peptidoglycan cross-linking. Our main aim in the study is to screen possible inhibitors against AmpC / β - lactamase (an enzyme responsible for antimicrobial activity in Pseudomonas aeruginosa), through virtual screening of 1364 NCI (National Cancer Institute) diversity set II compounds. Homology Model of AmpC / β - lactamase was constructed using MODELLER and the Model was validated using PROCHECK and Verify 3D programs to obtain a stable structure, which was further used for virtual screening of NCI (National Cancer Institute) diversity set II compounds through molecular Docking studies using Autodock. The amino acid sequence of the β - lactamase was also subjected to ScanProsite web server to find any pattern present in the sequence. After the prediction of 3-dimensional model of AmpC/ β-lactamase, the possible Active sites ofβ - lactamase were determined using LIGSITE(csc) and CastP web servers simultaneously. The Docked complexes were validated and Enumerated based on the Autodock Scoring function to pick out the best inhibitor based on Autodock energy score. Thus from the entire 1364 NCI diversity set II compounds which were Docked, the best four docking solutions were selected (ZINC12670903, ZINC17465965, ZINC11681166 and ZINC13099024). Further the Complexes were analyzed through LIGPLOT for their interaction for the 4 best docked NCI diversity set II compounds. Thus from the Complex scoring and binding ability it is deciphered that these NCI diversity set II compounds could be promising inhibitors for Pseudomonas aeruginosa using AmpC /β - lactamase as Drug target yet pharmacological studies have to confirm it.

No MeSH data available.


Related in: MedlinePlus

(A) The final model of AmpC / β ‐ lactamase; (B) Validation of the model using Ramachandran plot computed with the PROCHECKprogram with 95.1 % of the residues in the most favored regions.
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Related In: Results  -  Collection


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Figure 1: (A) The final model of AmpC / β ‐ lactamase; (B) Validation of the model using Ramachandran plot computed with the PROCHECKprogram with 95.1 % of the residues in the most favored regions.

Mentions: The hypothetical protein models generated in the modeling procedurewere analyzed online by submitting to NIH MBI Laboratory forStructural Genomics and Proteomics' SAVES server. Validity reportsgenerated by PROCHECK and Verfiy_3D judged accuracy of theprotein models. A comparison of the results obtained from the abovementionedvalidation tools, showed that one of the models generated byModeller is more acceptable in comparison to the others and wasselected for further studies. For the final selected model Ramachandranplot generated by PROCHECK showed 95.1% residues in the mostfavored region (Figure 1). The compatibility of the atomic model (3D)with its own amino acid sequence (1D) computed by Verfy_3Dreported 100.00% of the residues having an average 3D-1D score > 0.2 .


Virtual screening of AmpC/β-lactamase as target for antimicrobial resistance in Pseudomonas aeruginosa.

Farmer R, Gautam B, Singh S, Yadav PK, Jain PA - Bioinformation (2010)

(A) The final model of AmpC / β ‐ lactamase; (B) Validation of the model using Ramachandran plot computed with the PROCHECKprogram with 95.1 % of the residues in the most favored regions.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2957765&req=5

Figure 1: (A) The final model of AmpC / β ‐ lactamase; (B) Validation of the model using Ramachandran plot computed with the PROCHECKprogram with 95.1 % of the residues in the most favored regions.
Mentions: The hypothetical protein models generated in the modeling procedurewere analyzed online by submitting to NIH MBI Laboratory forStructural Genomics and Proteomics' SAVES server. Validity reportsgenerated by PROCHECK and Verfiy_3D judged accuracy of theprotein models. A comparison of the results obtained from the abovementionedvalidation tools, showed that one of the models generated byModeller is more acceptable in comparison to the others and wasselected for further studies. For the final selected model Ramachandranplot generated by PROCHECK showed 95.1% residues in the mostfavored region (Figure 1). The compatibility of the atomic model (3D)with its own amino acid sequence (1D) computed by Verfy_3Dreported 100.00% of the residues having an average 3D-1D score > 0.2 .

Bottom Line: Thus from the entire 1364 NCI diversity set II compounds which were Docked, the best four docking solutions were selected (ZINC12670903, ZINC17465965, ZINC11681166 and ZINC13099024).Further the Complexes were analyzed through LIGPLOT for their interaction for the 4 best docked NCI diversity set II compounds.Thus from the Complex scoring and binding ability it is deciphered that these NCI diversity set II compounds could be promising inhibitors for Pseudomonas aeruginosa using AmpC /β - lactamase as Drug target yet pharmacological studies have to confirm it.

View Article: PubMed Central - PubMed

Affiliation: Department of Computational Biology and Bioinformatics, Sam Higginbottom Institute of Agricultural, Technology and Sciences, Allahabad 211007, U.P, India.

ABSTRACT
AmpC is a group I, class C -lactamase present in most Enterobacteriaceae and in Pseudomonas aeruginosa and other nonfermenting gram-negative bacilli. The β-lactam class of antibiotics is one of the most important structural classes of antibacterial compounds and act by inhibiting the bacterial D ,D - transpeptidases that are responsible for the final step of peptidoglycan cross-linking. Our main aim in the study is to screen possible inhibitors against AmpC / β - lactamase (an enzyme responsible for antimicrobial activity in Pseudomonas aeruginosa), through virtual screening of 1364 NCI (National Cancer Institute) diversity set II compounds. Homology Model of AmpC / β - lactamase was constructed using MODELLER and the Model was validated using PROCHECK and Verify 3D programs to obtain a stable structure, which was further used for virtual screening of NCI (National Cancer Institute) diversity set II compounds through molecular Docking studies using Autodock. The amino acid sequence of the β - lactamase was also subjected to ScanProsite web server to find any pattern present in the sequence. After the prediction of 3-dimensional model of AmpC/ β-lactamase, the possible Active sites ofβ - lactamase were determined using LIGSITE(csc) and CastP web servers simultaneously. The Docked complexes were validated and Enumerated based on the Autodock Scoring function to pick out the best inhibitor based on Autodock energy score. Thus from the entire 1364 NCI diversity set II compounds which were Docked, the best four docking solutions were selected (ZINC12670903, ZINC17465965, ZINC11681166 and ZINC13099024). Further the Complexes were analyzed through LIGPLOT for their interaction for the 4 best docked NCI diversity set II compounds. Thus from the Complex scoring and binding ability it is deciphered that these NCI diversity set II compounds could be promising inhibitors for Pseudomonas aeruginosa using AmpC /β - lactamase as Drug target yet pharmacological studies have to confirm it.

No MeSH data available.


Related in: MedlinePlus