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Adaptive evolution and elucidating the potential inhibitor against schizophrenia to target DAOA (G72) isoforms.

Sehgal SA, Mannan S, Kanwal S, Naveed I, Mir A - Drug Des Devel Ther (2015)

Bottom Line: The C-terminal of selected isoforms is conserved, and binding was observed on the conserved region of isoforms.We propose that selected inhibitor might be more potent on the basis of binding energy values.Overall, the findings of this study may be helpful in designing novel therapeutic targets to cure SZ.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioinformatics and Biotechnology, International Islamic University, Islamabad, Pakistan ; Department of Biosciences, COMSATS Institute of Information Technology, Sahiwal, Pakistan.

ABSTRACT
Schizophrenia (SZ), a chronic mental and heritable disorder characterized by neurophysiological impairment and neuropsychological abnormalities, is strongly associated with D-amino acid oxidase activator (DAOA, G72). Research studies emphasized that overexpression of DAOA may be responsible for improper functioning of neurotransmitters, resulting in neurological disorders like SZ. In the present study, a hybrid approach of comparative modeling and molecular docking followed by inhibitor identification and structure modeling was employed. Screening was performed by two-dimensional similarity search against selected inhibitor, keeping in view the physiochemical properties of the inhibitor. Here, we report an inhibitor compound which showed maximum binding affinity against four selected isoforms of DAOA. Docking studies revealed that Glu-53, Thr-54, Lys-58, Val-85, Ser-86, Tyr-87, Leu-88, Glu-90, Leu-95, Val-98, Ser-100, Glu-112, Tyr-116, Lys-120, Asp-121, and Arg-122 are critical residues for receptor-ligand interaction. The C-terminal of selected isoforms is conserved, and binding was observed on the conserved region of isoforms. We propose that selected inhibitor might be more potent on the basis of binding energy values. Further analysis of this inhibitor through site-directed mutagenesis could be helpful for exploring the details of ligand-binding pockets. Overall, the findings of this study may be helpful in designing novel therapeutic targets to cure SZ.

No MeSH data available.


Related in: MedlinePlus

Multiple sequence alignment of DAOA isoforms (DAOA-153, DAOA-125, DAOA-82) with conserved region.Note: Conserved region in three isoforms are represented in orchid color in three-dimensional structures and also colored in sequence.
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f4-dddt-9-3471: Multiple sequence alignment of DAOA isoforms (DAOA-153, DAOA-125, DAOA-82) with conserved region.Note: Conserved region in three isoforms are represented in orchid color in three-dimensional structures and also colored in sequence.

Mentions: It was observed that Ser-100 of DAOA-153, Ser-29 of DAOA-82, and Ser-72 of DAOA-125 (Figure 4) having good binding interactions with the same docked ligand. The residues having different positions due to variation in the size of isoforms are indicated with matching superscript letters in Table 2. The conserved region has same binding residues but have different positions due to different size of isoforms (Figure 5). In an effort to comprehend the better interactions observed between ligand and amino acid residues in the active site of protein, a plot of amino acids–ligand interactions were generated employing Ligplot and Chimera 1.6 as shown in Figure 6.


Adaptive evolution and elucidating the potential inhibitor against schizophrenia to target DAOA (G72) isoforms.

Sehgal SA, Mannan S, Kanwal S, Naveed I, Mir A - Drug Des Devel Ther (2015)

Multiple sequence alignment of DAOA isoforms (DAOA-153, DAOA-125, DAOA-82) with conserved region.Note: Conserved region in three isoforms are represented in orchid color in three-dimensional structures and also colored in sequence.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4498731&req=5

f4-dddt-9-3471: Multiple sequence alignment of DAOA isoforms (DAOA-153, DAOA-125, DAOA-82) with conserved region.Note: Conserved region in three isoforms are represented in orchid color in three-dimensional structures and also colored in sequence.
Mentions: It was observed that Ser-100 of DAOA-153, Ser-29 of DAOA-82, and Ser-72 of DAOA-125 (Figure 4) having good binding interactions with the same docked ligand. The residues having different positions due to variation in the size of isoforms are indicated with matching superscript letters in Table 2. The conserved region has same binding residues but have different positions due to different size of isoforms (Figure 5). In an effort to comprehend the better interactions observed between ligand and amino acid residues in the active site of protein, a plot of amino acids–ligand interactions were generated employing Ligplot and Chimera 1.6 as shown in Figure 6.

Bottom Line: The C-terminal of selected isoforms is conserved, and binding was observed on the conserved region of isoforms.We propose that selected inhibitor might be more potent on the basis of binding energy values.Overall, the findings of this study may be helpful in designing novel therapeutic targets to cure SZ.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioinformatics and Biotechnology, International Islamic University, Islamabad, Pakistan ; Department of Biosciences, COMSATS Institute of Information Technology, Sahiwal, Pakistan.

ABSTRACT
Schizophrenia (SZ), a chronic mental and heritable disorder characterized by neurophysiological impairment and neuropsychological abnormalities, is strongly associated with D-amino acid oxidase activator (DAOA, G72). Research studies emphasized that overexpression of DAOA may be responsible for improper functioning of neurotransmitters, resulting in neurological disorders like SZ. In the present study, a hybrid approach of comparative modeling and molecular docking followed by inhibitor identification and structure modeling was employed. Screening was performed by two-dimensional similarity search against selected inhibitor, keeping in view the physiochemical properties of the inhibitor. Here, we report an inhibitor compound which showed maximum binding affinity against four selected isoforms of DAOA. Docking studies revealed that Glu-53, Thr-54, Lys-58, Val-85, Ser-86, Tyr-87, Leu-88, Glu-90, Leu-95, Val-98, Ser-100, Glu-112, Tyr-116, Lys-120, Asp-121, and Arg-122 are critical residues for receptor-ligand interaction. The C-terminal of selected isoforms is conserved, and binding was observed on the conserved region of isoforms. We propose that selected inhibitor might be more potent on the basis of binding energy values. Further analysis of this inhibitor through site-directed mutagenesis could be helpful for exploring the details of ligand-binding pockets. Overall, the findings of this study may be helpful in designing novel therapeutic targets to cure SZ.

No MeSH data available.


Related in: MedlinePlus