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Mol Inform. 2019 Feb 6. doi: 10.1002/minf.201800118. [Epub ahead of print]

Identification of New Potent Acetylcholinesterase Inhibitors Using Virtual Screening and In Vitro Approaches.

Author information

1
Laboratory of Applied Biochemistry, Department of Biochemistry and Cellular and Molecular Biology, Faculty of Natural and Life Sciences, University Mentouri Brothers Constantine 1, Algeria.
2
Chemistry, Modeling and Imaging for Biology (CMIB), Institut Curie, PSL Research University, CNRS UMR 9187 - INSERM U1196, Paris-Saclay University, F-91405, Orsay, France.
3
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, LabEx LERMIT, 91198, Gif-sur-Yvette, France.
4
Department of Nephrology and Dialysis, AP-HP, Tenon Hospital, INSERM UMR_S 1155, 75020, Paris, France.
5
Chemical library, Institut Curie-CNRS, UMR9187-U1196 and UMR3666-U1143, F-91405, Orsay, France.
6
Laboratory of Biochemistry, Division of Biotechnology and health, Biotechnology research Center (CRBt), Constantine, Algeria.
7
Laboratory of Genetics and Biochemistry Plant Biotechnology, Faculty of Natural and Life Sciences, University Mentouri Brothers Constantine 1, Algeria.

Abstract

Acetylcholinesterase (AChE) is currently the most favorable target for the symptomatic treatment and reduction of Alzheimer's disease (AD). In order to identify new potent inhibitors of this enzyme, we describe herein a new structure-based virtual screening (SBVS) using the Institut Curie-CNRS chemical library (ICCL), which contained at the screening date 14307 compounds. The strategy undertaken in this work consisted of the use of several docking programs in SBVS calculations followed by the application of a consensus method (vSDC) and a scrupulous visual analysis. It allowed us to obtain a high degree of success, with a yield of almost 86 %, since 12 hits were identified among only 14 molecules tested in vitro. Still more remarkably, 6 of these hits were more active than galantamine, the reference inhibitor. These hits were predicted to have good ADMET properties. The two most promising compounds can serve as leads for AD treatment.

KEYWORDS:

Acetylcholinesterase; Alzheimer's disease; Virtual screening; inhibitory activity; vSDC

PMID:
30725535
DOI:
10.1002/minf.201800118

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