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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

Three-dimensional structure of the four DAOA isoforms.
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f2-dddt-9-3471: Three-dimensional structure of the four DAOA isoforms.

Mentions: Evaluation tools showed the reliability and efficacy of DAOA three-dimensional predicted structures (Figure 2). Favored and outlier regions of predicted models were detected in Ramachandran plot and mentioned in Table 1. DAOA-153 and DAOA-126 showed four and three residues in outlier regions, respectively. No amino acid residue was observed in outlier region, and all the amino acids of the DAOA-82 were observed in favored and allowed region. In DAOA-125, only one residue was observed in outlier region. Poor rotamers and outliers were corrected to refine the predicted models of DAOA.


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)

Three-dimensional structure of the four DAOA isoforms.
© Copyright Policy
Related In: Results  -  Collection

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

f2-dddt-9-3471: Three-dimensional structure of the four DAOA isoforms.
Mentions: Evaluation tools showed the reliability and efficacy of DAOA three-dimensional predicted structures (Figure 2). Favored and outlier regions of predicted models were detected in Ramachandran plot and mentioned in Table 1. DAOA-153 and DAOA-126 showed four and three residues in outlier regions, respectively. No amino acid residue was observed in outlier region, and all the amino acids of the DAOA-82 were observed in favored and allowed region. In DAOA-125, only one residue was observed in outlier region. Poor rotamers and outliers were corrected to refine the predicted models of DAOA.

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