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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).Human AChE was found to be most approptiate target site as compared to commonly used Torpedo AChE.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

hAChE 3D structure modeled by Phyre2.(A) Cartoon representation, key residues are represented in green sticks with the catalytic triad in red. (B) Surface representation, looking down catalytic groove. Images generated by using PyMOL v1.3.
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pone.0136509.g002: hAChE 3D structure modeled by Phyre2.(A) Cartoon representation, key residues are represented in green sticks with the catalytic triad in red. (B) Surface representation, looking down catalytic groove. Images generated by using PyMOL v1.3.

Mentions: The Phyre2 (Protein Homology/AnalogY Recognition Engine) is one of most popular methods for protein structure prediction [26]. The server found maximum similarity of the target sequence provided (GI: 295321523) with fold library id: d2ha2a1. It used X-ray crystal structure d2ha2a1 as template and modeled the target. A total of 536 residues out of 583 residues (92% of sequence) were modeled with 100% confidence. The software classified the enzyme as superfamily alpha/beta-hydrolases and family as acetylcholinesterase-like enzyme. The modeled hAChE structure alignment with PDB entries 2X8B_A and 4EY4 (the two crystal structures available for human enzyme in PDB) by using FATCAT algorithm, showed 99.3% and 99% similarity with RMSD 0.32 and 0.65 respectively. The high percentage similarity indicates that the modeled hAChE (99% similar) is a better target for molecular docking as compared to torpedo enzyme (75% similar). Images of modeled hAChE indicating the active site is shown in Fig 2A and 2B.


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)

hAChE 3D structure modeled by Phyre2.(A) Cartoon representation, key residues are represented in green sticks with the catalytic triad in red. (B) Surface representation, looking down catalytic groove. Images generated by using PyMOL v1.3.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0136509.g002: hAChE 3D structure modeled by Phyre2.(A) Cartoon representation, key residues are represented in green sticks with the catalytic triad in red. (B) Surface representation, looking down catalytic groove. Images generated by using PyMOL v1.3.
Mentions: The Phyre2 (Protein Homology/AnalogY Recognition Engine) is one of most popular methods for protein structure prediction [26]. The server found maximum similarity of the target sequence provided (GI: 295321523) with fold library id: d2ha2a1. It used X-ray crystal structure d2ha2a1 as template and modeled the target. A total of 536 residues out of 583 residues (92% of sequence) were modeled with 100% confidence. The software classified the enzyme as superfamily alpha/beta-hydrolases and family as acetylcholinesterase-like enzyme. The modeled hAChE structure alignment with PDB entries 2X8B_A and 4EY4 (the two crystal structures available for human enzyme in PDB) by using FATCAT algorithm, showed 99.3% and 99% similarity with RMSD 0.32 and 0.65 respectively. The high percentage similarity indicates that the modeled hAChE (99% similar) is a better target for molecular docking as compared to torpedo enzyme (75% similar). Images of modeled hAChE indicating the active site is shown in Fig 2A and 2B.

Bottom Line: The disease leads to irreversible loss of neurons that result in reduced level of acetylcholine neurotransmitter (ACh).Human AChE was found to be most approptiate target site as compared to commonly used Torpedo AChE.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