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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

Overexpression of DAOA in brain and cause of SZ.Notes: DAOA, which activates DAO gene, is an enzyme that degrades D-serine (D-ser) amino acid. Serine racemase (SRR) synthesizes D-ser from L-serine. Alanine-serine-cysteine transporter (ASCT) is the primary means of synaptic D-ser transport. D-ser acts as the co-agonist at the glycine site of N-methyl-D-aspartic acid (NMDA) receptor. Hypo function of NMDA receptor complex is the potential mechanism for schizophrenia (SZ) pathogenesis. Hyperfunction of DAO decreases the D-ser level. The level of D-ser is reduced in serum and cerebrospinal regions of SZ patients. Overexpression of DAOA enhance the activity of DAO results in the reduction of D-ser and cause of SZ.
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f1-dddt-9-3471: Overexpression of DAOA in brain and cause of SZ.Notes: DAOA, which activates DAO gene, is an enzyme that degrades D-serine (D-ser) amino acid. Serine racemase (SRR) synthesizes D-ser from L-serine. Alanine-serine-cysteine transporter (ASCT) is the primary means of synaptic D-ser transport. D-ser acts as the co-agonist at the glycine site of N-methyl-D-aspartic acid (NMDA) receptor. Hypo function of NMDA receptor complex is the potential mechanism for schizophrenia (SZ) pathogenesis. Hyperfunction of DAO decreases the D-ser level. The level of D-ser is reduced in serum and cerebrospinal regions of SZ patients. Overexpression of DAOA enhance the activity of DAO results in the reduction of D-ser and cause of SZ.

Mentions: SZ patients show DAOA overexpression in the dorsolateral prefrontal cortex when compared with healthy controls.14 SZ susceptibility genes have been identified in genetic studies,15–18 but genetic interactions among SZ genes and their interplay with clinical subtypes and neurobiological abnormalities remains obscure. The product of DAO is an enzyme that degrades D-serine amino acid which acts as a co-agonist at the glycine site of the N-methyl-D-aspartic acid (NMDA) receptors.19 The product of DAOA (G72) activates the DAO enzyme.6 The biological function of DAOA and DAO are involved in the hypothesized hypofunction of NMDA receptor complex as the prospective pathogenesis of SZ (Figure 1).20


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)

Overexpression of DAOA in brain and cause of SZ.Notes: DAOA, which activates DAO gene, is an enzyme that degrades D-serine (D-ser) amino acid. Serine racemase (SRR) synthesizes D-ser from L-serine. Alanine-serine-cysteine transporter (ASCT) is the primary means of synaptic D-ser transport. D-ser acts as the co-agonist at the glycine site of N-methyl-D-aspartic acid (NMDA) receptor. Hypo function of NMDA receptor complex is the potential mechanism for schizophrenia (SZ) pathogenesis. Hyperfunction of DAO decreases the D-ser level. The level of D-ser is reduced in serum and cerebrospinal regions of SZ patients. Overexpression of DAOA enhance the activity of DAO results in the reduction of D-ser and cause of SZ.
© Copyright Policy
Related In: Results  -  Collection

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

f1-dddt-9-3471: Overexpression of DAOA in brain and cause of SZ.Notes: DAOA, which activates DAO gene, is an enzyme that degrades D-serine (D-ser) amino acid. Serine racemase (SRR) synthesizes D-ser from L-serine. Alanine-serine-cysteine transporter (ASCT) is the primary means of synaptic D-ser transport. D-ser acts as the co-agonist at the glycine site of N-methyl-D-aspartic acid (NMDA) receptor. Hypo function of NMDA receptor complex is the potential mechanism for schizophrenia (SZ) pathogenesis. Hyperfunction of DAO decreases the D-ser level. The level of D-ser is reduced in serum and cerebrospinal regions of SZ patients. Overexpression of DAOA enhance the activity of DAO results in the reduction of D-ser and cause of SZ.
Mentions: SZ patients show DAOA overexpression in the dorsolateral prefrontal cortex when compared with healthy controls.14 SZ susceptibility genes have been identified in genetic studies,15–18 but genetic interactions among SZ genes and their interplay with clinical subtypes and neurobiological abnormalities remains obscure. The product of DAO is an enzyme that degrades D-serine amino acid which acts as a co-agonist at the glycine site of the N-methyl-D-aspartic acid (NMDA) receptors.19 The product of DAOA (G72) activates the DAO enzyme.6 The biological function of DAOA and DAO are involved in the hypothesized hypofunction of NMDA receptor complex as the prospective pathogenesis of SZ (Figure 1).20

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