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Combined QSAR, molecular docking and molecular dynamics study on new Acetylcholinesterase and Butyrylcholinesterase inhibitors.
Comput Biol Chem. 2018 Jun; 74:304-326.CB

Abstract

BACKGROUND AND PURPOSE

This work deals with several molecular modeling methods used to discover new therapeutic agents for treating the Alzheimer's disease (AD). The cholinergic hypothesis was initially presented over 30 years ago and suggests that a dysfunction of acetylcholine containing neurons in the brain. Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE) are of the keys targets of drugs for treating AD.

METHODS

QSAR, Molecular Docking/Dynamics and ADME properties were carried out in order to study 36 compounds that belong to the 4-[(diethylamino)methyl]-phenol derivatives and test their AChE and BuChE inhibitory activities, MOE, HyperChem and others softwares were used to find the best compounds with high affinity.

RESULTS

The QSAR models exhibited good statistical values for both targets AChE (R2adj = 0.660, q2 = 0.70, F-ratio = 18.008) and BuChE (R2adj = 0.726, q2 = 0.75, F-ratio = 31.864). The interactions between the studied inhibitors and our targets were further explored through molecular docking and molecular dynamics simulations. A few key residues (TRP279, TYR334, PHE330 and TRP84) at the binding site of AChE and key residues (HIS438, TYR332, PHE329 and TRP82) at the binding site of BuChE were identified.

CONCLUSION

Based on this study compounds 23 and 28 have no violated Lipinski's rule of five and thus, showing the possibility of being potential candidates for further studies in drug development process against the AChE and BuChE targets respectively.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Daoud I
University Mohamed Khider, Department of Matter Sciences, BP 145 RP, 07000, Biskra, Algeria; Laboratory of Natural and bio-actives Substances, Tlemcen University, Faculty of Science, P.O. Box 119, Tlemcen, Algeria. Electronic address: i.daoud@univ-biskra.dz.
Melkemi N
Group of Computational and Pharmaceutical Chemistry LMCE Laboratory, University of Biskra, 07000, Algeria.
Salah T
Group of Computational and Pharmaceutical Chemistry LMCE Laboratory, University of Biskra, 07000, Algeria.
Ghalem S
Laboratory of Natural and bio-actives Substances, Tlemcen University, Faculty of Science, P.O. Box 119, Tlemcen, Algeria.

MeSH

AcetylcholinesteraseButyrylcholinesteraseCholinesterase InhibitorsHumansMolecular Docking SimulationMolecular Dynamics SimulationMolecular StructurePhenolsQuantitative Structure-Activity RelationshipQuantum TheoryStructure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29747032

Citation

Daoud, Ismail, et al. "Combined QSAR, Molecular Docking and Molecular Dynamics Study On New Acetylcholinesterase and Butyrylcholinesterase Inhibitors." Computational Biology and Chemistry, vol. 74, 2018, pp. 304-326.
Daoud I, Melkemi N, Salah T, et al. Combined QSAR, molecular docking and molecular dynamics study on new Acetylcholinesterase and Butyrylcholinesterase inhibitors. Comput Biol Chem. 2018;74:304-326.
Daoud, I., Melkemi, N., Salah, T., & Ghalem, S. (2018). Combined QSAR, molecular docking and molecular dynamics study on new Acetylcholinesterase and Butyrylcholinesterase inhibitors. Computational Biology and Chemistry, 74, 304-326. https://doi.org/10.1016/j.compbiolchem.2018.03.021
Daoud I, et al. Combined QSAR, Molecular Docking and Molecular Dynamics Study On New Acetylcholinesterase and Butyrylcholinesterase Inhibitors. Comput Biol Chem. 2018;74:304-326. PubMed PMID: 29747032.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combined QSAR, molecular docking and molecular dynamics study on new Acetylcholinesterase and Butyrylcholinesterase inhibitors. AU - Daoud,Ismail, AU - Melkemi,Nadjib, AU - Salah,Toufik, AU - Ghalem,Said, Y1 - 2018/03/29/ PY - 2017/12/17/received PY - 2018/03/01/revised PY - 2018/03/17/accepted PY - 2018/5/11/pubmed PY - 2018/8/30/medline PY - 2018/5/11/entrez KW - AChE/BuChE KW - ADME KW - Molecular docking KW - Molecular dynamics KW - QSAR SP - 304 EP - 326 JF - Computational biology and chemistry JO - Comput Biol Chem VL - 74 N2 - BACKGROUND AND PURPOSE: This work deals with several molecular modeling methods used to discover new therapeutic agents for treating the Alzheimer's disease (AD). The cholinergic hypothesis was initially presented over 30 years ago and suggests that a dysfunction of acetylcholine containing neurons in the brain. Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE) are of the keys targets of drugs for treating AD. METHODS: QSAR, Molecular Docking/Dynamics and ADME properties were carried out in order to study 36 compounds that belong to the 4-[(diethylamino)methyl]-phenol derivatives and test their AChE and BuChE inhibitory activities, MOE, HyperChem and others softwares were used to find the best compounds with high affinity. RESULTS: The QSAR models exhibited good statistical values for both targets AChE (R2adj = 0.660, q2 = 0.70, F-ratio = 18.008) and BuChE (R2adj = 0.726, q2 = 0.75, F-ratio = 31.864). The interactions between the studied inhibitors and our targets were further explored through molecular docking and molecular dynamics simulations. A few key residues (TRP279, TYR334, PHE330 and TRP84) at the binding site of AChE and key residues (HIS438, TYR332, PHE329 and TRP82) at the binding site of BuChE were identified. CONCLUSION: Based on this study compounds 23 and 28 have no violated Lipinski's rule of five and thus, showing the possibility of being potential candidates for further studies in drug development process against the AChE and BuChE targets respectively. SN - 1476-928X UR - https://www.unboundmedicine.com/medline/citation/29747032/Combined_QSAR_molecular_docking_and_molecular_dynamics_study_on_new_Acetylcholinesterase_and_Butyrylcholinesterase_inhibitors_ DB - PRIME DP - Unbound Medicine ER -