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Structure based prediction of functional sites with potential inhibitors to Nudix enzymes from disease causing microbes.

Sharma A, Tendulkar AV, Wangikar PP - Bioinformation (2011)

Bottom Line: The substrate ADP-Ribose was docked with the Nudix enzymes, 2B06 (Docking energy -15.68 Kcal/mol) and 2AZW (Docking energy -10.86 Kcal/mol) with the higher affinity and the lower docking energy as compared to other substrates.The inhibitor compounds AMPCPR and CID14258187 were docked well as compared to other compounds.The compound CID14258187 was also in agreement with Lipinski rule of 5 for drug likeness properties.

View Article: PubMed Central - PubMed

ABSTRACT
The functional sites were predicted for Nudix enzymes from pathogenic microorganisms such as Streprococcus pneumonia (2B06) and Enterococcus faecalis (2AZW). Their structures are already determined, however, no data is reported about their functional sites, substrates and inhibitors. Therefore, we report prediction of functional sites in these Nudix enzymes via Geometric Invariant (GI) technique (Construct different geometries of peptides which remain unchanged). The GI method enumerated 2B06: RA57, EA58, EA61, EA62 and 2AZW: RA62, EA63, EA66, EA67 as putative functional sites in these Nudix enzymes. In addition, the substrate was predicted via Molecular docking (Docking of substrates against whole structure of Nudix enzymes). The substrate ADP-Ribose was docked with the Nudix enzymes, 2B06 (Docking energy -15.68 Kcal/mol) and 2AZW (Docking energy -10.86 Kcal/mol) with the higher affinity and the lower docking energy as compared to other substrates. The residues EA62 in 2B06 and RA62 in 2AZW make hydrogen bonds with the ADP-ribose. Furthermore, we screened 51 inhibitor compounds against structures of 2B06 and 2AZW. The inhibitor compounds AMPCPR and CID14258187 were docked well as compared to other compounds. The compound CID14258187 was also in agreement with Lipinski rule of 5 for drug likeness properties. Therefore, our findings of functional sites, substrates and inhibitors for these Nudix enzymes may help in structure based drug designing against Streprococcus pneumonia and Enterococcus faecalis.

No MeSH data available.


Related in: MedlinePlus

Overall schematic for prediction of functional sites, substrates and inhibitors for Structural Genomics Nudix enzymes 2B06 and 2AZW from Streptococcus pneumoniae and Enterococcus faecalis.  It can be broadly divided into the following steps: (1a) Building library of functional sites from known proteins (templates), (1b) Enumeration of substructures from Nudix enzymes 2B06 and 2AZW and mapping them to space spanned by Geometric Invariants (GIs), (2) Matching substructures of enzymes with  functional sites in the library  to obtain putative functional site, (3) Based on matching templates, obtain a list of potential substrates for docking analysis, (4) Molecular docking of substrates against Nudix targets: (4a) Blind docking of substrates against the target and (4b) Refined docking of substrates against the target, (5) Search putative inhibitors of Nudix enzymes from literature and similar compounds from PUBCHEM database, (6) Docking of these inhibitors  (7) Docking analysis that includes (i) Analysis of substrate and inhibitor binding in the cavity of Nudix targets, (ii) Extraction of active site residues with in 6A0 radius around the substrate binding site and (iii) hydrogen bond analysis at the predicted functional site.
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Figure 1: Overall schematic for prediction of functional sites, substrates and inhibitors for Structural Genomics Nudix enzymes 2B06 and 2AZW from Streptococcus pneumoniae and Enterococcus faecalis. It can be broadly divided into the following steps: (1a) Building library of functional sites from known proteins (templates), (1b) Enumeration of substructures from Nudix enzymes 2B06 and 2AZW and mapping them to space spanned by Geometric Invariants (GIs), (2) Matching substructures of enzymes with functional sites in the library to obtain putative functional site, (3) Based on matching templates, obtain a list of potential substrates for docking analysis, (4) Molecular docking of substrates against Nudix targets: (4a) Blind docking of substrates against the target and (4b) Refined docking of substrates against the target, (5) Search putative inhibitors of Nudix enzymes from literature and similar compounds from PUBCHEM database, (6) Docking of these inhibitors (7) Docking analysis that includes (i) Analysis of substrate and inhibitor binding in the cavity of Nudix targets, (ii) Extraction of active site residues with in 6A0 radius around the substrate binding site and (iii) hydrogen bond analysis at the predicted functional site.

Mentions: We used molecular docking method for prediction of substrates and their binding sites in 2B06 and 2AZW. The substrates were selected from pdb files and literature of the template proteins present in the matched cluster (from GI method). The SMILES strings of substrates were obtained from PUBCHEM database (http://pubchem.ncbi.nlm.nih.gov/) and converted in to 3D via using CORINA server (www.molecular-networks.com/ online_demos/corina_demo.html). The substrates were docked against the Nudix target 2B06 and 2AZW in two settings: Blind docking and Refined docking. The blind docking considers the whole structure of the Nudix enzymes as docking target, while in refined docking, we specifies the functional sites ( predicted by our GI method) as docking target and generates the grid map with grid points spacing at 0.375A. The docking experiments were performed via using AUTODOCK4.0 [16]. All docking parameters were set to be default (Figure 1).


Structure based prediction of functional sites with potential inhibitors to Nudix enzymes from disease causing microbes.

Sharma A, Tendulkar AV, Wangikar PP - Bioinformation (2011)

Overall schematic for prediction of functional sites, substrates and inhibitors for Structural Genomics Nudix enzymes 2B06 and 2AZW from Streptococcus pneumoniae and Enterococcus faecalis.  It can be broadly divided into the following steps: (1a) Building library of functional sites from known proteins (templates), (1b) Enumeration of substructures from Nudix enzymes 2B06 and 2AZW and mapping them to space spanned by Geometric Invariants (GIs), (2) Matching substructures of enzymes with  functional sites in the library  to obtain putative functional site, (3) Based on matching templates, obtain a list of potential substrates for docking analysis, (4) Molecular docking of substrates against Nudix targets: (4a) Blind docking of substrates against the target and (4b) Refined docking of substrates against the target, (5) Search putative inhibitors of Nudix enzymes from literature and similar compounds from PUBCHEM database, (6) Docking of these inhibitors  (7) Docking analysis that includes (i) Analysis of substrate and inhibitor binding in the cavity of Nudix targets, (ii) Extraction of active site residues with in 6A0 radius around the substrate binding site and (iii) hydrogen bond analysis at the predicted functional site.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3046039&req=5

Figure 1: Overall schematic for prediction of functional sites, substrates and inhibitors for Structural Genomics Nudix enzymes 2B06 and 2AZW from Streptococcus pneumoniae and Enterococcus faecalis. It can be broadly divided into the following steps: (1a) Building library of functional sites from known proteins (templates), (1b) Enumeration of substructures from Nudix enzymes 2B06 and 2AZW and mapping them to space spanned by Geometric Invariants (GIs), (2) Matching substructures of enzymes with functional sites in the library to obtain putative functional site, (3) Based on matching templates, obtain a list of potential substrates for docking analysis, (4) Molecular docking of substrates against Nudix targets: (4a) Blind docking of substrates against the target and (4b) Refined docking of substrates against the target, (5) Search putative inhibitors of Nudix enzymes from literature and similar compounds from PUBCHEM database, (6) Docking of these inhibitors (7) Docking analysis that includes (i) Analysis of substrate and inhibitor binding in the cavity of Nudix targets, (ii) Extraction of active site residues with in 6A0 radius around the substrate binding site and (iii) hydrogen bond analysis at the predicted functional site.
Mentions: We used molecular docking method for prediction of substrates and their binding sites in 2B06 and 2AZW. The substrates were selected from pdb files and literature of the template proteins present in the matched cluster (from GI method). The SMILES strings of substrates were obtained from PUBCHEM database (http://pubchem.ncbi.nlm.nih.gov/) and converted in to 3D via using CORINA server (www.molecular-networks.com/ online_demos/corina_demo.html). The substrates were docked against the Nudix target 2B06 and 2AZW in two settings: Blind docking and Refined docking. The blind docking considers the whole structure of the Nudix enzymes as docking target, while in refined docking, we specifies the functional sites ( predicted by our GI method) as docking target and generates the grid map with grid points spacing at 0.375A. The docking experiments were performed via using AUTODOCK4.0 [16]. All docking parameters were set to be default (Figure 1).

Bottom Line: The substrate ADP-Ribose was docked with the Nudix enzymes, 2B06 (Docking energy -15.68 Kcal/mol) and 2AZW (Docking energy -10.86 Kcal/mol) with the higher affinity and the lower docking energy as compared to other substrates.The inhibitor compounds AMPCPR and CID14258187 were docked well as compared to other compounds.The compound CID14258187 was also in agreement with Lipinski rule of 5 for drug likeness properties.

View Article: PubMed Central - PubMed

ABSTRACT
The functional sites were predicted for Nudix enzymes from pathogenic microorganisms such as Streprococcus pneumonia (2B06) and Enterococcus faecalis (2AZW). Their structures are already determined, however, no data is reported about their functional sites, substrates and inhibitors. Therefore, we report prediction of functional sites in these Nudix enzymes via Geometric Invariant (GI) technique (Construct different geometries of peptides which remain unchanged). The GI method enumerated 2B06: RA57, EA58, EA61, EA62 and 2AZW: RA62, EA63, EA66, EA67 as putative functional sites in these Nudix enzymes. In addition, the substrate was predicted via Molecular docking (Docking of substrates against whole structure of Nudix enzymes). The substrate ADP-Ribose was docked with the Nudix enzymes, 2B06 (Docking energy -15.68 Kcal/mol) and 2AZW (Docking energy -10.86 Kcal/mol) with the higher affinity and the lower docking energy as compared to other substrates. The residues EA62 in 2B06 and RA62 in 2AZW make hydrogen bonds with the ADP-ribose. Furthermore, we screened 51 inhibitor compounds against structures of 2B06 and 2AZW. The inhibitor compounds AMPCPR and CID14258187 were docked well as compared to other compounds. The compound CID14258187 was also in agreement with Lipinski rule of 5 for drug likeness properties. Therefore, our findings of functional sites, substrates and inhibitors for these Nudix enzymes may help in structure based drug designing against Streprococcus pneumonia and Enterococcus faecalis.

No MeSH data available.


Related in: MedlinePlus