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Designing Second Generation Anti-Alzheimer Compounds as Inhibitors of Human Acetylcholinesterase: Computational Screening of Synthetic Molecules and Dietary Phytochemicals.

Amat-Ur-Rasool H, Ahmed M - PLoS ONE (2015)

Bottom Line: The disease leads to irreversible loss of neurons that result in reduced level of acetylcholine neurotransmitter (ACh).Molecular docking results of the database retrieved (synthetic chemicals and dietary phytochemicals) and self-drawn ligands were compared with Food and Drug Administration (FDA) approved drugs against AD as controls.Using computational methods, compounds present in online chemical databases can be screened to design more efficient and safer drugs against cognitive symptoms of AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan; National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.

ABSTRACT
Alzheimer's disease (AD), a big cause of memory loss, is a progressive neurodegenerative disorder. The disease leads to irreversible loss of neurons that result in reduced level of acetylcholine neurotransmitter (ACh). The reduction of ACh level impairs brain functioning. One aspect of AD therapy is to maintain ACh level up to a safe limit, by blocking acetylcholinesterase (AChE), an enzyme that is naturally responsible for its degradation. This research presents an in-silico screening and designing of hAChE inhibitors as potential anti-Alzheimer drugs. Molecular docking results of the database retrieved (synthetic chemicals and dietary phytochemicals) and self-drawn ligands were compared with Food and Drug Administration (FDA) approved drugs against AD as controls. Furthermore, computational ADME studies were performed on the hits to assess their safety. Human AChE was found to be most approptiate target site as compared to commonly used Torpedo AChE. Among the tested dietry phytochemicals, berberastine, berberine, yohimbine, sanguinarine, elemol and naringenin are the worth mentioning phytochemicals as potential anti-Alzheimer drugs The synthetic leads were mostly dual binding site inhibitors with two binding subunits linked by a carbon chain i.e. second generation AD drugs. Fifteen new heterodimers were designed that were computationally more efficient inhibitors than previously reported compounds. Using computational methods, compounds present in online chemical databases can be screened to design more efficient and safer drugs against cognitive symptoms of AD.

No MeSH data available.


Related in: MedlinePlus

Visual results of docking of best designed AD drug candidate, berberastine-5C-pyrimidine, into modeled hAChE.(A) Ligand attachment conformation along the active site groove shown by solid surface ligand site. (B) Ligand attached with different residues of catalytic site, represented by sticks and colored according to the element type and element name is labeled. Active site residues are represented by sticks and enzyme by cartoons. Hydrogen bonding shown by yellow dashes and distance measured in Å.
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pone.0136509.g004: Visual results of docking of best designed AD drug candidate, berberastine-5C-pyrimidine, into modeled hAChE.(A) Ligand attachment conformation along the active site groove shown by solid surface ligand site. (B) Ligand attached with different residues of catalytic site, represented by sticks and colored according to the element type and element name is labeled. Active site residues are represented by sticks and enzyme by cartoons. Hydrogen bonding shown by yellow dashes and distance measured in Å.

Mentions: One step forward, by considering the novel “multi-target-directed strategy” i.e. designing a molecule with dual or multiple binding sites [47], new heterodimers were planned. On the basis of structural analysis of synthetic and phytochemical leads (Table 1) new heterodimers were designed as combinations of natural alkaloids berberastine and berberine with tacrine and pyrimidine rings that are active components of top synthetic leads. These heterodimers can be potential second generation AD drugs in future. As inhibitors of the human enzyme instead of torpedo they are more specific in their activity, and fulfillment of druglikeliness criteria makes them orally safer. The 2D structure of the top five newly designed drugs along with their score comparison to controls is shown in Table 1. Present study demonstrates that, the designed lead berberastine-5C-pyrimidine is 91% more potent than tacrine, 25% more potent than donepezil and 10% more potent than the best synthetic database lead. Visual results for berberastine-5C-pyrimidine docking with the modeled hAChE (Fig 4A) shows that the pyrimidine ring blocks the catalytic site, five carbon chain span along the length of catalytic groove and berberastine binds to the peripheral site. Fig 4B shows O-OH type hydrogen bonding of ligand with TRP-286, TYR-124 and SER-125 residues of hAChE. The distances of hydrogen bonds were kept at < 3.50 Å cutoff.


Designing Second Generation Anti-Alzheimer Compounds as Inhibitors of Human Acetylcholinesterase: Computational Screening of Synthetic Molecules and Dietary Phytochemicals.

Amat-Ur-Rasool H, Ahmed M - PLoS ONE (2015)

Visual results of docking of best designed AD drug candidate, berberastine-5C-pyrimidine, into modeled hAChE.(A) Ligand attachment conformation along the active site groove shown by solid surface ligand site. (B) Ligand attached with different residues of catalytic site, represented by sticks and colored according to the element type and element name is labeled. Active site residues are represented by sticks and enzyme by cartoons. Hydrogen bonding shown by yellow dashes and distance measured in Å.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556483&req=5

pone.0136509.g004: Visual results of docking of best designed AD drug candidate, berberastine-5C-pyrimidine, into modeled hAChE.(A) Ligand attachment conformation along the active site groove shown by solid surface ligand site. (B) Ligand attached with different residues of catalytic site, represented by sticks and colored according to the element type and element name is labeled. Active site residues are represented by sticks and enzyme by cartoons. Hydrogen bonding shown by yellow dashes and distance measured in Å.
Mentions: One step forward, by considering the novel “multi-target-directed strategy” i.e. designing a molecule with dual or multiple binding sites [47], new heterodimers were planned. On the basis of structural analysis of synthetic and phytochemical leads (Table 1) new heterodimers were designed as combinations of natural alkaloids berberastine and berberine with tacrine and pyrimidine rings that are active components of top synthetic leads. These heterodimers can be potential second generation AD drugs in future. As inhibitors of the human enzyme instead of torpedo they are more specific in their activity, and fulfillment of druglikeliness criteria makes them orally safer. The 2D structure of the top five newly designed drugs along with their score comparison to controls is shown in Table 1. Present study demonstrates that, the designed lead berberastine-5C-pyrimidine is 91% more potent than tacrine, 25% more potent than donepezil and 10% more potent than the best synthetic database lead. Visual results for berberastine-5C-pyrimidine docking with the modeled hAChE (Fig 4A) shows that the pyrimidine ring blocks the catalytic site, five carbon chain span along the length of catalytic groove and berberastine binds to the peripheral site. Fig 4B shows O-OH type hydrogen bonding of ligand with TRP-286, TYR-124 and SER-125 residues of hAChE. The distances of hydrogen bonds were kept at < 3.50 Å cutoff.

Bottom Line: The disease leads to irreversible loss of neurons that result in reduced level of acetylcholine neurotransmitter (ACh).Molecular docking results of the database retrieved (synthetic chemicals and dietary phytochemicals) and self-drawn ligands were compared with Food and Drug Administration (FDA) approved drugs against AD as controls.Using computational methods, compounds present in online chemical databases can be screened to design more efficient and safer drugs against cognitive symptoms of AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan; National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.

ABSTRACT
Alzheimer's disease (AD), a big cause of memory loss, is a progressive neurodegenerative disorder. The disease leads to irreversible loss of neurons that result in reduced level of acetylcholine neurotransmitter (ACh). The reduction of ACh level impairs brain functioning. One aspect of AD therapy is to maintain ACh level up to a safe limit, by blocking acetylcholinesterase (AChE), an enzyme that is naturally responsible for its degradation. This research presents an in-silico screening and designing of hAChE inhibitors as potential anti-Alzheimer drugs. Molecular docking results of the database retrieved (synthetic chemicals and dietary phytochemicals) and self-drawn ligands were compared with Food and Drug Administration (FDA) approved drugs against AD as controls. Furthermore, computational ADME studies were performed on the hits to assess their safety. Human AChE was found to be most approptiate target site as compared to commonly used Torpedo AChE. Among the tested dietry phytochemicals, berberastine, berberine, yohimbine, sanguinarine, elemol and naringenin are the worth mentioning phytochemicals as potential anti-Alzheimer drugs The synthetic leads were mostly dual binding site inhibitors with two binding subunits linked by a carbon chain i.e. second generation AD drugs. Fifteen new heterodimers were designed that were computationally more efficient inhibitors than previously reported compounds. Using computational methods, compounds present in online chemical databases can be screened to design more efficient and safer drugs against cognitive symptoms of AD.

No MeSH data available.


Related in: MedlinePlus