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BioMed Research International Volume 2017 ,2017-01-19
Pharmacoinformatics, Adaptive Evolution, and Elucidation of Six Novel Compounds for Schizophrenia Treatment by Targeting DAOA (G72) Isoforms
Research Article
Sheikh Arslan Sehgal 1 , 2 , 3
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DOI:10.1155/2017/5925714
Received 2016-10-11, accepted for publication 2016-12-22, Published 2016-12-22
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摘要

Studies on Schizophrenia so far reveal a complex picture of neurological malfunctioning reported to be strongly associated with DAOA. Detailed sequence analyses proved DAOA as a primate specific gene having conserved gene desert region on both upstream and downstream region. The analyses of 10 MB chromosomal region of primates, birds, rodents, and reptiles having DAOA evidenced the conserved part in primates and in the rest of species, while DAOA is only present in primates. DAOA has four isoforms having one interaction partner DAO. Protein-protein analyses of four DAOA isoforms with DAO were performed individually and find potential interacting residues computationally. It was observed that molecular docking of approved FDA drugs revealed efficient results but there was no common drug with effective binding to all DAOA isoforms. Library of compounds was constructed by virtual screening of 2D similarity search against recommended SZ drugs in conjunction with their physiochemical properties. Molecular docking resulted in six novel compounds exhibiting maximum binding affinity with selected four DAOA isoforms. However not the entire schizophrenic population responds to the single drug and interestingly in this study six novel compounds having promising results and same binding site to that DAOA that may be used to interact with DAO against four DAOA isoforms were observed.

授权许可

Copyright © 2017 Sheikh Arslan Sehgal. 2017
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

图表

Gene desert on both regions of DAOA in human chromosome 13.

Conserved gene desert in analyzed species.

Phylogenetic tree of DAOA constructed by neighbor-joining (NJ) method and absence of DAOA in rodents, chicken, and reptiles.

Comparative evaluation analyses of generated 3D models based on ERRAT quality factor (blue line), favored region (red line), allowed region (green line), and outliers (purple line).

Comparative evaluation analyses of generated 3D models based on ERRAT quality factor (blue line), favored region (red line), allowed region (green line), and outliers (purple line).

Comparative evaluation analyses of generated 3D models based on ERRAT quality factor (blue line), favored region (red line), allowed region (green line), and outliers (purple line).

Comparative evaluation analyses of generated 3D models based on ERRAT quality factor (blue line), favored region (red line), allowed region (green line), and outliers (purple line).

3D structure of DAOA isoforms.

Two-dimensional structures of selected drugs. (a) Chlorpromazine, (b) Memantine, (c) Iloperidone, (d) Galantamine, (e) Haloperidol, (f) Clozapine, (g) Modafinil, and (h) Lamictal.

Two-dimensional structures of selected drugs. (a) Chlorpromazine, (b) Memantine, (c) Iloperidone, (d) Galantamine, (e) Haloperidol, (f) Clozapine, (g) Modafinil, and (h) Lamictal.

Two-dimensional structures of selected drugs. (a) Chlorpromazine, (b) Memantine, (c) Iloperidone, (d) Galantamine, (e) Haloperidol, (f) Clozapine, (g) Modafinil, and (h) Lamictal.

Two-dimensional structures of selected drugs. (a) Chlorpromazine, (b) Memantine, (c) Iloperidone, (d) Galantamine, (e) Haloperidol, (f) Clozapine, (g) Modafinil, and (h) Lamictal.

Two-dimensional structures of selected drugs. (a) Chlorpromazine, (b) Memantine, (c) Iloperidone, (d) Galantamine, (e) Haloperidol, (f) Clozapine, (g) Modafinil, and (h) Lamictal.

Two-dimensional structures of selected drugs. (a) Chlorpromazine, (b) Memantine, (c) Iloperidone, (d) Galantamine, (e) Haloperidol, (f) Clozapine, (g) Modafinil, and (h) Lamictal.

Two-dimensional structures of selected drugs. (a) Chlorpromazine, (b) Memantine, (c) Iloperidone, (d) Galantamine, (e) Haloperidol, (f) Clozapine, (g) Modafinil, and (h) Lamictal.

Two-dimensional structures of selected drugs. (a) Chlorpromazine, (b) Memantine, (c) Iloperidone, (d) Galantamine, (e) Haloperidol, (f) Clozapine, (g) Modafinil, and (h) Lamictal.

2D structure of scrutinized 6 novel molecules: (a) SA-1, (b) SA-3, (c) SA-11, (d) SA-68, (e) SA-110, and (f) SA-111.

2D structure of scrutinized 6 novel molecules: (a) SA-1, (b) SA-3, (c) SA-11, (d) SA-68, (e) SA-110, and (f) SA-111.

2D structure of scrutinized 6 novel molecules: (a) SA-1, (b) SA-3, (c) SA-11, (d) SA-68, (e) SA-110, and (f) SA-111.

2D structure of scrutinized 6 novel molecules: (a) SA-1, (b) SA-3, (c) SA-11, (d) SA-68, (e) SA-110, and (f) SA-111.

2D structure of scrutinized 6 novel molecules: (a) SA-1, (b) SA-3, (c) SA-11, (d) SA-68, (e) SA-110, and (f) SA-111.

2D structure of scrutinized 6 novel molecules: (a) SA-1, (b) SA-3, (c) SA-11, (d) SA-68, (e) SA-110, and (f) SA-111.

The DAOA isoforms interactions with appropriate drugs. The residues analyzed from AutoDock 4 were represented with orange, gold residues with gold, and AutoDock Vina with cornflower blue color. (a) Galantamine interaction with DAOA-82. (b) Modafinil interaction with DAOA-125. (c) Chlorpromazine interacting residues with DAOA-126. (d) Haloperidol with DAOA-153.

The DAOA isoforms interactions with appropriate drugs. The residues analyzed from AutoDock 4 were represented with orange, gold residues with gold, and AutoDock Vina with cornflower blue color. (a) Galantamine interaction with DAOA-82. (b) Modafinil interaction with DAOA-125. (c) Chlorpromazine interacting residues with DAOA-126. (d) Haloperidol with DAOA-153.

The DAOA isoforms interactions with appropriate drugs. The residues analyzed from AutoDock 4 were represented with orange, gold residues with gold, and AutoDock Vina with cornflower blue color. (a) Galantamine interaction with DAOA-82. (b) Modafinil interaction with DAOA-125. (c) Chlorpromazine interacting residues with DAOA-126. (d) Haloperidol with DAOA-153.

The DAOA isoforms interactions with appropriate drugs. The residues analyzed from AutoDock 4 were represented with orange, gold residues with gold, and AutoDock Vina with cornflower blue color. (a) Galantamine interaction with DAOA-82. (b) Modafinil interaction with DAOA-125. (c) Chlorpromazine interacting residues with DAOA-126. (d) Haloperidol with DAOA-153.

通讯作者

Sheikh Arslan Sehgal.Department of Biosciences, COMSATS Institute of Information Technology, Sahiwal, Pakistan, comsats.edu.pk;State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China, cas.cn;University of Chinese Academy of Sciences, Beijing, China, ucas.ac.cn.arslansehgal@yahoo.com

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Sheikh Arslan Sehgal. Pharmacoinformatics, Adaptive Evolution, and Elucidation of Six Novel Compounds for Schizophrenia Treatment by Targeting DAOA (G72) Isoforms. BioMed Research International ,Vol.2017(2017)

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