Abstract
Nineteen new derivatives based on the structure of marine natural product tasiamide B were designed, synthesized, and evaluated for their inhibitory activity against BACE1, a potential therapeutic target for Alzheimer's disease. The hydrophobic substituents Val at P₃ position, Leu at P₁' position, Ala at P₂' position, and Phe at P₃' position were found to significantly affect the inhibition. Free carboxylic acid at C-terminus was also found to be important to the activity. In addition, the structure-activity relationships (SARs) were supported by molecular docking simulation.
Keywords:
Alzheimer’s disease; BACE1 inhibitor; Docking; Synthesis; β-Secretase.
Copyright © 2015. Published by Elsevier Ltd.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / metabolism
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / metabolism
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Dose-Response Relationship, Drug
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Drug Design*
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Humans
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Molecular Docking Simulation
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Molecular Structure
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Oligopeptides / chemistry*
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Oligopeptides / pharmacology
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology*
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Structure-Activity Relationship
Substances
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Oligopeptides
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Protease Inhibitors
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tasiamide B
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human