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Molecular modeling, dynamics studies and virtual screening of Fructose 1, 6 biphosphate aldolase-II in community acquired- methicillin resistant Staphylococcus aureus (CA-MRSA).

Yadav PK, Singh G, Gautam B, Singh S, Yadav M, Srivastav U, Singh B - Bioinformation (2013)

Bottom Line: The MDS results suggest that the modeled structure is stable.Based on the docking energy scores, it was found that top four ligands i.e. ZINC01690699, ZINC13154304, ZINC29590257 and ZINC29590259 were having lower energy scores which reveal higher binding affinity towards the active site of FBA.However, pharmacological studies are required to confirm the inhibitory activity of these ligands against the FBA in CA-MRSA.

View Article: PubMed Central - PubMed

Affiliation: Department of Computational Biology & Bioinformatics, Sam Higginbottom Institute of Agriculture, Technology & Sciences (Deemed University), Allahabad-211007, India.

ABSTRACT
Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has recently emerged as a nosocomial pathogen to the community which commonly causes skin and soft-tissue infections (SSTIs). This strain (MW2) has now become resistant to the most of the beta-lactam antibiotics; therefore it is the urgent need to identify the novel drug targets. Recently fructose 1,6 biphosphate aldolase-II (FBA) has been identified as potential drug target in CA-MRSA. The FBA catalyses the retro-ketolic cleavage of fructose-1,6-bisphosphate (FBP) to yield dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (G3P) in glycolytic pathway. In the present research work the 3D structure of FBA was predicted using the homology modeling method followed by validation. The molecular dynamics simulation (MDS) of the predicted model was carried out using the 2000 ps time scale and 1000000 steps. The MDS results suggest that the modeled structure is stable. The predicted model of FBA was used for virtual screening against the NCI diversity subset-II ligand databases which contain 1364 compounds. Based on the docking energy scores, it was found that top four ligands i.e. ZINC01690699, ZINC13154304, ZINC29590257 and ZINC29590259 were having lower energy scores which reveal higher binding affinity towards the active site of FBA. These ligands might act as potent inhibitors for the FBA so that the menace of antimicrobial resistance in CA-MRSA can be conquered. However, pharmacological studies are required to confirm the inhibitory activity of these ligands against the FBA in CA-MRSA.

No MeSH data available.


Related in: MedlinePlus

(A) The 3D model of fructose biphosphate aldolase; (B) The Ramachandran plot of modeled structure validated byPROCHECK program.
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Figure 1: (A) The 3D model of fructose biphosphate aldolase; (B) The Ramachandran plot of modeled structure validated byPROCHECK program.

Mentions: The availability of 3D structure of the target is foremost step toproceed for the structure-based drug designing. Since the 3Dstructure of fructose 1, 6-biphosphate aldolase (FBA) in CAMRSAis not yet available in the Protein Data Bank (PDB),therefore unknown structure of FBA was predicted by thehomology modeling method using the HHPred server [13]. Thisserver uses Modeller 9v9 program for 3D structure prediction.To identify the best template(s) for the target protein, databasesearching was carried out using the BLASTp program. Atemplate (PDB ID: 3Q94_A) having 76% sequence identity, 1.2e-100 E-value and alignment score(S) of 711.74, was selected forgenerating the 3D model of the FBA. The sequence identitiesand E-values are important parameters which are consideredduring the template(s) selection. The templates which arehaving high sequence identity, high alignment score(S), andlow E-value are often selected for the reliable model generationof the target protein. The expect(E) value is a parameter thatmeasures the significance of similarity between sequencesduring the database searching. This value decreasesexponentially with the Score(S) that is assigned to a matchbetween two sequences. The multiple sequence alignment wasperformed for the target-template sequences using theclustalW2 program and aligned target-template sequences weresubmitted to the HHPred server. Then 3D model of the FBAwas created (Figure 1A). In order to evaluate the stereochemicalproperties as well as to find any anomaly in the predictedmodel, it was uploaded to the SAVES server. Procheck [20]results show that on the Ramachandran plot [21] , 94.7% aminoacid residues fall in core (most favored) regions, 4.9% inallowed, 0.4% in generously allowed, and no any residue fallsin disallowed regions (Figure 1B).


Molecular modeling, dynamics studies and virtual screening of Fructose 1, 6 biphosphate aldolase-II in community acquired- methicillin resistant Staphylococcus aureus (CA-MRSA).

Yadav PK, Singh G, Gautam B, Singh S, Yadav M, Srivastav U, Singh B - Bioinformation (2013)

(A) The 3D model of fructose biphosphate aldolase; (B) The Ramachandran plot of modeled structure validated byPROCHECK program.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3569604&req=5

Figure 1: (A) The 3D model of fructose biphosphate aldolase; (B) The Ramachandran plot of modeled structure validated byPROCHECK program.
Mentions: The availability of 3D structure of the target is foremost step toproceed for the structure-based drug designing. Since the 3Dstructure of fructose 1, 6-biphosphate aldolase (FBA) in CAMRSAis not yet available in the Protein Data Bank (PDB),therefore unknown structure of FBA was predicted by thehomology modeling method using the HHPred server [13]. Thisserver uses Modeller 9v9 program for 3D structure prediction.To identify the best template(s) for the target protein, databasesearching was carried out using the BLASTp program. Atemplate (PDB ID: 3Q94_A) having 76% sequence identity, 1.2e-100 E-value and alignment score(S) of 711.74, was selected forgenerating the 3D model of the FBA. The sequence identitiesand E-values are important parameters which are consideredduring the template(s) selection. The templates which arehaving high sequence identity, high alignment score(S), andlow E-value are often selected for the reliable model generationof the target protein. The expect(E) value is a parameter thatmeasures the significance of similarity between sequencesduring the database searching. This value decreasesexponentially with the Score(S) that is assigned to a matchbetween two sequences. The multiple sequence alignment wasperformed for the target-template sequences using theclustalW2 program and aligned target-template sequences weresubmitted to the HHPred server. Then 3D model of the FBAwas created (Figure 1A). In order to evaluate the stereochemicalproperties as well as to find any anomaly in the predictedmodel, it was uploaded to the SAVES server. Procheck [20]results show that on the Ramachandran plot [21] , 94.7% aminoacid residues fall in core (most favored) regions, 4.9% inallowed, 0.4% in generously allowed, and no any residue fallsin disallowed regions (Figure 1B).

Bottom Line: The MDS results suggest that the modeled structure is stable.Based on the docking energy scores, it was found that top four ligands i.e. ZINC01690699, ZINC13154304, ZINC29590257 and ZINC29590259 were having lower energy scores which reveal higher binding affinity towards the active site of FBA.However, pharmacological studies are required to confirm the inhibitory activity of these ligands against the FBA in CA-MRSA.

View Article: PubMed Central - PubMed

Affiliation: Department of Computational Biology & Bioinformatics, Sam Higginbottom Institute of Agriculture, Technology & Sciences (Deemed University), Allahabad-211007, India.

ABSTRACT
Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has recently emerged as a nosocomial pathogen to the community which commonly causes skin and soft-tissue infections (SSTIs). This strain (MW2) has now become resistant to the most of the beta-lactam antibiotics; therefore it is the urgent need to identify the novel drug targets. Recently fructose 1,6 biphosphate aldolase-II (FBA) has been identified as potential drug target in CA-MRSA. The FBA catalyses the retro-ketolic cleavage of fructose-1,6-bisphosphate (FBP) to yield dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (G3P) in glycolytic pathway. In the present research work the 3D structure of FBA was predicted using the homology modeling method followed by validation. The molecular dynamics simulation (MDS) of the predicted model was carried out using the 2000 ps time scale and 1000000 steps. The MDS results suggest that the modeled structure is stable. The predicted model of FBA was used for virtual screening against the NCI diversity subset-II ligand databases which contain 1364 compounds. Based on the docking energy scores, it was found that top four ligands i.e. ZINC01690699, ZINC13154304, ZINC29590257 and ZINC29590259 were having lower energy scores which reveal higher binding affinity towards the active site of FBA. These ligands might act as potent inhibitors for the FBA so that the menace of antimicrobial resistance in CA-MRSA can be conquered. However, pharmacological studies are required to confirm the inhibitory activity of these ligands against the FBA in CA-MRSA.

No MeSH data available.


Related in: MedlinePlus