Limits...
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

Alignment of human and Torpedo californica AChE.(A)Amino acid sequence alignment generated by RMBOSS-Needle. (B) 3D structure alignment of PDB entry 2X8B chain A for human and PDB entry 1EVE for Torpedo californica AChE generated by online tool Aladyn.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4556483&req=5

pone.0136509.g001: Alignment of human and Torpedo californica AChE.(A)Amino acid sequence alignment generated by RMBOSS-Needle. (B) 3D structure alignment of PDB entry 2X8B chain A for human and PDB entry 1EVE for Torpedo californica AChE generated by online tool Aladyn.

Mentions: Pairwise alignment of human and Torpedo californica AChE sequences showed multiple mismatches and gaps between the two sequences. EMBOSS-Needle calculated 53.3% identity and 69.6% similarity between the two sequences using EBLOSUM62 matrix. The alignment generated is shown in Fig 1A. As the tertiary structures protein of remained more conserved in evolution than their amino acid sequences, alignment was performed between 3D structures of hAChE (2X8B_A: 536 a.a) and TcAChE (1EVE: 534 a.a). A total of 517 amino acid residues were perfectly aligned between the two proteins and root mean square distance (RMSD) of the aligned regions was 1.8 Å. By using FATCAT algorithm [28] percentage similarity was calculated between the two structures that came out to be 75%. 3D alignment of the two structures is shown in Fig 1B. The difference between the human and torpedo enzyme at the levels of sequence and structure can probably have significant effect on ligand binding conformations.


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)

Alignment of human and Torpedo californica AChE.(A)Amino acid sequence alignment generated by RMBOSS-Needle. (B) 3D structure alignment of PDB entry 2X8B chain A for human and PDB entry 1EVE for Torpedo californica AChE generated by online tool Aladyn.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0136509.g001: Alignment of human and Torpedo californica AChE.(A)Amino acid sequence alignment generated by RMBOSS-Needle. (B) 3D structure alignment of PDB entry 2X8B chain A for human and PDB entry 1EVE for Torpedo californica AChE generated by online tool Aladyn.
Mentions: Pairwise alignment of human and Torpedo californica AChE sequences showed multiple mismatches and gaps between the two sequences. EMBOSS-Needle calculated 53.3% identity and 69.6% similarity between the two sequences using EBLOSUM62 matrix. The alignment generated is shown in Fig 1A. As the tertiary structures protein of remained more conserved in evolution than their amino acid sequences, alignment was performed between 3D structures of hAChE (2X8B_A: 536 a.a) and TcAChE (1EVE: 534 a.a). A total of 517 amino acid residues were perfectly aligned between the two proteins and root mean square distance (RMSD) of the aligned regions was 1.8 Å. By using FATCAT algorithm [28] percentage similarity was calculated between the two structures that came out to be 75%. 3D alignment of the two structures is shown in Fig 1B. The difference between the human and torpedo enzyme at the levels of sequence and structure can probably have significant effect on ligand binding conformations.

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