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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

Receptor-ligand interaction is shown. (A) ZINC12670903 hydrogen bonded with Ser 64 OH, Lys 316 NH and Thr 317 OH at a distanceof 2.79 Å, 2.75 Å and 2.53 Å, respectively whereas Gln 120, Tyr 151, Tyr 223, Ser 319, Thr 320 and Asn 321 are non-ligand residues involved inhydrophobic contact(s). (B) ZINC17465965 hydrogen bonded with Ser 64 OH, Arg 149 NH, Tyr 151 OH, Asn 153 NH, Thr 317 OH and Asn 347NH at a distance of 2.87 Å, 2.68 Å, 2.90 Å, 2.97 Å, 2.57 Å and 3.29 Å respectively whereas Ala 293, Ser 319 and Thr 320 are non-ligand residuesinvolved in hydrophobic contact(s). (C) ZINC11681166 hydrogen bonded with Ser 64 OH, Tyr 151 OH and Asn 344 NH at a distance of 2.35 Å,2.44 Å and 2.79 Å respectively whereas Thr 290, Ala 293, Ser 319, Thr 320 and Asn 321 are non-ligand residues involved in hydrophobiccontact(s). (D) ZINC13099024 hydrogen bonded with Ser 64 OH, Tyr 151 OH, Gly 214 NH and Thr 317 OH at distance of 2.76 Å, 3.09 Å, 3.25 Åand 2.79 Å respectively whereas Val 213, Tyr 223, Thr 320 and Asn 321 are non-ligand residues involved in hydrophobic contact(s).
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Figure 3: Receptor-ligand interaction is shown. (A) ZINC12670903 hydrogen bonded with Ser 64 OH, Lys 316 NH and Thr 317 OH at a distanceof 2.79 Å, 2.75 Å and 2.53 Å, respectively whereas Gln 120, Tyr 151, Tyr 223, Ser 319, Thr 320 and Asn 321 are non-ligand residues involved inhydrophobic contact(s). (B) ZINC17465965 hydrogen bonded with Ser 64 OH, Arg 149 NH, Tyr 151 OH, Asn 153 NH, Thr 317 OH and Asn 347NH at a distance of 2.87 Å, 2.68 Å, 2.90 Å, 2.97 Å, 2.57 Å and 3.29 Å respectively whereas Ala 293, Ser 319 and Thr 320 are non-ligand residuesinvolved in hydrophobic contact(s). (C) ZINC11681166 hydrogen bonded with Ser 64 OH, Tyr 151 OH and Asn 344 NH at a distance of 2.35 Å,2.44 Å and 2.79 Å respectively whereas Thr 290, Ala 293, Ser 319, Thr 320 and Asn 321 are non-ligand residues involved in hydrophobiccontact(s). (D) ZINC13099024 hydrogen bonded with Ser 64 OH, Tyr 151 OH, Gly 214 NH and Thr 317 OH at distance of 2.76 Å, 3.09 Å, 3.25 Åand 2.79 Å respectively whereas Val 213, Tyr 223, Thr 320 and Asn 321 are non-ligand residues involved in hydrophobic contact(s).

Mentions: To understand the interaction between β ‐ lactamase and the fourcompounds from the NCI Diversity Set II, complexes were generatedusing AutodockTools for outputs of Autodock solutions. LIGPLOTwere run for all the four complexes (Figure 3). It is evident from theanalysis of the Docked complex that the Ligands are located in thecenter of the Active site, and is stabilized by hydrogen bondinginteractions. The interaction analysis shows that Ser 64, Tyr 151 andThr 317 are important anchoring residues for β ‐ lactamase and themain contributors towards compound interaction. Though theinteraction energy does not include the contribution from the water ofthe extended compound structure, this preliminary data along with thelist of hydrogen bond interactions between the compounds and theActive site residues clearly supports that Ser 64, Tyr 151 and Thr 317are more preferred residues in binding.


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)

Receptor-ligand interaction is shown. (A) ZINC12670903 hydrogen bonded with Ser 64 OH, Lys 316 NH and Thr 317 OH at a distanceof 2.79 Å, 2.75 Å and 2.53 Å, respectively whereas Gln 120, Tyr 151, Tyr 223, Ser 319, Thr 320 and Asn 321 are non-ligand residues involved inhydrophobic contact(s). (B) ZINC17465965 hydrogen bonded with Ser 64 OH, Arg 149 NH, Tyr 151 OH, Asn 153 NH, Thr 317 OH and Asn 347NH at a distance of 2.87 Å, 2.68 Å, 2.90 Å, 2.97 Å, 2.57 Å and 3.29 Å respectively whereas Ala 293, Ser 319 and Thr 320 are non-ligand residuesinvolved in hydrophobic contact(s). (C) ZINC11681166 hydrogen bonded with Ser 64 OH, Tyr 151 OH and Asn 344 NH at a distance of 2.35 Å,2.44 Å and 2.79 Å respectively whereas Thr 290, Ala 293, Ser 319, Thr 320 and Asn 321 are non-ligand residues involved in hydrophobiccontact(s). (D) ZINC13099024 hydrogen bonded with Ser 64 OH, Tyr 151 OH, Gly 214 NH and Thr 317 OH at distance of 2.76 Å, 3.09 Å, 3.25 Åand 2.79 Å respectively whereas Val 213, Tyr 223, Thr 320 and Asn 321 are non-ligand residues involved in hydrophobic contact(s).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 3: Receptor-ligand interaction is shown. (A) ZINC12670903 hydrogen bonded with Ser 64 OH, Lys 316 NH and Thr 317 OH at a distanceof 2.79 Å, 2.75 Å and 2.53 Å, respectively whereas Gln 120, Tyr 151, Tyr 223, Ser 319, Thr 320 and Asn 321 are non-ligand residues involved inhydrophobic contact(s). (B) ZINC17465965 hydrogen bonded with Ser 64 OH, Arg 149 NH, Tyr 151 OH, Asn 153 NH, Thr 317 OH and Asn 347NH at a distance of 2.87 Å, 2.68 Å, 2.90 Å, 2.97 Å, 2.57 Å and 3.29 Å respectively whereas Ala 293, Ser 319 and Thr 320 are non-ligand residuesinvolved in hydrophobic contact(s). (C) ZINC11681166 hydrogen bonded with Ser 64 OH, Tyr 151 OH and Asn 344 NH at a distance of 2.35 Å,2.44 Å and 2.79 Å respectively whereas Thr 290, Ala 293, Ser 319, Thr 320 and Asn 321 are non-ligand residues involved in hydrophobiccontact(s). (D) ZINC13099024 hydrogen bonded with Ser 64 OH, Tyr 151 OH, Gly 214 NH and Thr 317 OH at distance of 2.76 Å, 3.09 Å, 3.25 Åand 2.79 Å respectively whereas Val 213, Tyr 223, Thr 320 and Asn 321 are non-ligand residues involved in hydrophobic contact(s).
Mentions: To understand the interaction between β ‐ lactamase and the fourcompounds from the NCI Diversity Set II, complexes were generatedusing AutodockTools for outputs of Autodock solutions. LIGPLOTwere run for all the four complexes (Figure 3). It is evident from theanalysis of the Docked complex that the Ligands are located in thecenter of the Active site, and is stabilized by hydrogen bondinginteractions. The interaction analysis shows that Ser 64, Tyr 151 andThr 317 are important anchoring residues for β ‐ lactamase and themain contributors towards compound interaction. Though theinteraction energy does not include the contribution from the water ofthe extended compound structure, this preliminary data along with thelist of hydrogen bond interactions between the compounds and theActive site residues clearly supports that Ser 64, Tyr 151 and Thr 317are more preferred residues in binding.

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