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Molecular-docking-guided design and synthesis of new IAA-tacrine hybrids as multifunctional AChE/BChE inhibitors.
Bioorg Chem. 2019 03; 83:277-288.BC

Abstract

A series of new indole-3-acetic acid (IAA)-tacrine hybrids as dual acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitors were designed and prepared based on the molecular docking mode of AChE with an IAA derivative (1a), a moderate AChE inhibitor identified by screening our compound library for anti-Alzheimer's disease (AD) drug leads. The enzyme assay results revealed that some hybrids, e.g. 5d and 5e, displayed potent dual in vitro inhibitory activities against AChE/BChE with IC50 values in low nanomolar range. Molecular modeling studies in tandem with kinetic analysis suggest that these hybrids target both catalytic active site and peripheral anionic site of cholinesterase (ChE). Molecular dynamic simulations and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) calculations indicate that 5e has more potent binding affinity than hit 1a, which may explain the stronger inhibitory effect of 5e on AChE. Furthermore, their predicted pharmacokinetic properties and in vitro influences on mouse brain neural network electrical activity were discussed. Taken together, compound 5e can be highlighted as a lead compound worthy of further optimization for designing new anti-AD drugs.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Cheng ZQ
School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
Zhu KK
School of Biological Science and Technology, University of Jinan, Jinan 250022, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Zhang J
School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
Song JL
School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
Muehlmann LA
Institute of Biological Sciences, University of Brasília, Brasilia 70910900, Brazil; Faculty of Ceilandia, University of Brasília, Brasilia 72220275, Brazil.
Jiang CS
School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: jiangchengshi-20@163.com.
Liu CL
Cambrian Discovery Inc., Dover, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: Changliang_Liu@hms.harvard.edu.
Zhang H
School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: bio_zhangh@ujn.edu.cn.

MeSH

AcetylcholinesteraseButyrylcholinesteraseCholinesterase InhibitorsHEK293 CellsHep G2 CellsHumansIndoleacetic AcidsKineticsLigandsMolecular Docking SimulationMolecular Dynamics SimulationMolecular StructureProtein BindingStructure-Activity RelationshipTacrine

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30391700

Citation

Cheng, Zhi-Qiang, et al. "Molecular-docking-guided Design and Synthesis of New IAA-tacrine Hybrids as Multifunctional AChE/BChE Inhibitors." Bioorganic Chemistry, vol. 83, 2019, pp. 277-288.
Cheng ZQ, Zhu KK, Zhang J, et al. Molecular-docking-guided design and synthesis of new IAA-tacrine hybrids as multifunctional AChE/BChE inhibitors. Bioorg Chem. 2019;83:277-288.
Cheng, Z. Q., Zhu, K. K., Zhang, J., Song, J. L., Muehlmann, L. A., Jiang, C. S., Liu, C. L., & Zhang, H. (2019). Molecular-docking-guided design and synthesis of new IAA-tacrine hybrids as multifunctional AChE/BChE inhibitors. Bioorganic Chemistry, 83, 277-288. https://doi.org/10.1016/j.bioorg.2018.10.057
Cheng ZQ, et al. Molecular-docking-guided Design and Synthesis of New IAA-tacrine Hybrids as Multifunctional AChE/BChE Inhibitors. Bioorg Chem. 2019;83:277-288. PubMed PMID: 30391700.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular-docking-guided design and synthesis of new IAA-tacrine hybrids as multifunctional AChE/BChE inhibitors. AU - Cheng,Zhi-Qiang, AU - Zhu,Kong-Kai, AU - Zhang,Juan, AU - Song,Jia-Li, AU - Muehlmann,Luis Alexandre, AU - Jiang,Cheng-Shi, AU - Liu,Chang-Liang, AU - Zhang,Hua, Y1 - 2018/10/29/ PY - 2018/08/28/received PY - 2018/10/26/revised PY - 2018/10/27/accepted PY - 2018/11/6/pubmed PY - 2020/1/8/medline PY - 2018/11/5/entrez KW - Alzheimer’s disease KW - Dual AChE/BChE inhibitor KW - IAA-tacrine hybrids KW - Molecular docking KW - Neural network electrical activity SP - 277 EP - 288 JF - Bioorganic chemistry JO - Bioorg Chem VL - 83 N2 - A series of new indole-3-acetic acid (IAA)-tacrine hybrids as dual acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitors were designed and prepared based on the molecular docking mode of AChE with an IAA derivative (1a), a moderate AChE inhibitor identified by screening our compound library for anti-Alzheimer's disease (AD) drug leads. The enzyme assay results revealed that some hybrids, e.g. 5d and 5e, displayed potent dual in vitro inhibitory activities against AChE/BChE with IC50 values in low nanomolar range. Molecular modeling studies in tandem with kinetic analysis suggest that these hybrids target both catalytic active site and peripheral anionic site of cholinesterase (ChE). Molecular dynamic simulations and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) calculations indicate that 5e has more potent binding affinity than hit 1a, which may explain the stronger inhibitory effect of 5e on AChE. Furthermore, their predicted pharmacokinetic properties and in vitro influences on mouse brain neural network electrical activity were discussed. Taken together, compound 5e can be highlighted as a lead compound worthy of further optimization for designing new anti-AD drugs. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/30391700/Molecular_docking_guided_design_and_synthesis_of_new_IAA_tacrine_hybrids_as_multifunctional_AChE/BChE_inhibitors_ DB - PRIME DP - Unbound Medicine ER -