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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

Superimposition of predicted functional  sites with the matching templates:  (a) The putative functional site of 2B06 (green) is superimposed with the residues of known Nudix protein 1SU2 (red) (RMSD 0.08 A0). The EA58 and EA61 make hydrogen bonds (blue) with surrounding water molecules (W403, W373 and W304). The water molecule W318 shares a hydrogen bond between glutamate residues at position 58 and 62.  (b) The putative functional site of 2AZW (green) is superimposed with the residues of known Nudix protein 1NQZ (red) (RMSD 0.16A0). The RA62 and EZ63 make hydrogen bond with W314 and W275 respectively. The glutamate residue EA66 is involved in making hydrogen bonds with two nearest water molecules W204 and W336. The water molecule W259 is sharing the hydrogen bonding between residues RA62 and EA63. The superimposition of patterns is performed by Discovery Studio (http://accelrys.com/products/discovery-studio/).
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Figure 3: Superimposition of predicted functional sites with the matching templates: (a) The putative functional site of 2B06 (green) is superimposed with the residues of known Nudix protein 1SU2 (red) (RMSD 0.08 A0). The EA58 and EA61 make hydrogen bonds (blue) with surrounding water molecules (W403, W373 and W304). The water molecule W318 shares a hydrogen bond between glutamate residues at position 58 and 62. (b) The putative functional site of 2AZW (green) is superimposed with the residues of known Nudix protein 1NQZ (red) (RMSD 0.16A0). The RA62 and EZ63 make hydrogen bond with W314 and W275 respectively. The glutamate residue EA66 is involved in making hydrogen bonds with two nearest water molecules W204 and W336. The water molecule W259 is sharing the hydrogen bonding between residues RA62 and EA63. The superimposition of patterns is performed by Discovery Studio (http://accelrys.com/products/discovery-studio/).

Mentions: We propose the following functional mechanism for 2B06: One of the catalytic residues, RA57, may form a hydrogen bond interaction with the nearest water molecules. The two glutamate residues, EA58 and EA61, may be involved in making coordination complex with a magnesium ion. Additionally, these glutamate residues may make hydrogen bonds with surrounding water molecules (W403, W373 and W304), while the water molecule, W318, may share a hydrogen bond with EA58 and EA62 (Figure 3(a)). On the other hand, in 2AZW: We found that the residues RA62 and EA63 are very close to magnesium ion and may form a coordination complex. These residues make hydrogen bonds with the nearest water molecules. For instance, RA62 makes a hydrogen bond with W314, while EA63 makes a hydrogen bond with W275. Similarly, the glutamate residue, EA66, makes hydrogen bonds with two nearest water molecules W204 and W336. The water molecule W259 shares a hydrogen bond between residues RA62 and EA63 (Figure 3(b)).


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

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

Superimposition of predicted functional  sites with the matching templates:  (a) The putative functional site of 2B06 (green) is superimposed with the residues of known Nudix protein 1SU2 (red) (RMSD 0.08 A0). The EA58 and EA61 make hydrogen bonds (blue) with surrounding water molecules (W403, W373 and W304). The water molecule W318 shares a hydrogen bond between glutamate residues at position 58 and 62.  (b) The putative functional site of 2AZW (green) is superimposed with the residues of known Nudix protein 1NQZ (red) (RMSD 0.16A0). The RA62 and EZ63 make hydrogen bond with W314 and W275 respectively. The glutamate residue EA66 is involved in making hydrogen bonds with two nearest water molecules W204 and W336. The water molecule W259 is sharing the hydrogen bonding between residues RA62 and EA63. The superimposition of patterns is performed by Discovery Studio (http://accelrys.com/products/discovery-studio/).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Superimposition of predicted functional sites with the matching templates: (a) The putative functional site of 2B06 (green) is superimposed with the residues of known Nudix protein 1SU2 (red) (RMSD 0.08 A0). The EA58 and EA61 make hydrogen bonds (blue) with surrounding water molecules (W403, W373 and W304). The water molecule W318 shares a hydrogen bond between glutamate residues at position 58 and 62. (b) The putative functional site of 2AZW (green) is superimposed with the residues of known Nudix protein 1NQZ (red) (RMSD 0.16A0). The RA62 and EZ63 make hydrogen bond with W314 and W275 respectively. The glutamate residue EA66 is involved in making hydrogen bonds with two nearest water molecules W204 and W336. The water molecule W259 is sharing the hydrogen bonding between residues RA62 and EA63. The superimposition of patterns is performed by Discovery Studio (http://accelrys.com/products/discovery-studio/).
Mentions: We propose the following functional mechanism for 2B06: One of the catalytic residues, RA57, may form a hydrogen bond interaction with the nearest water molecules. The two glutamate residues, EA58 and EA61, may be involved in making coordination complex with a magnesium ion. Additionally, these glutamate residues may make hydrogen bonds with surrounding water molecules (W403, W373 and W304), while the water molecule, W318, may share a hydrogen bond with EA58 and EA62 (Figure 3(a)). On the other hand, in 2AZW: We found that the residues RA62 and EA63 are very close to magnesium ion and may form a coordination complex. These residues make hydrogen bonds with the nearest water molecules. For instance, RA62 makes a hydrogen bond with W314, while EA63 makes a hydrogen bond with W275. Similarly, the glutamate residue, EA66, makes hydrogen bonds with two nearest water molecules W204 and W336. The water molecule W259 shares a hydrogen bond between residues RA62 and EA63 (Figure 3(b)).

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