Protonation states of the catalytic dyad of β-secretase (BACE1) in the presence of chemically diverse inhibitors: A molecular docking study

Arghya Barman, Rajeev Prabhakar

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28 Citations (Scopus)

Abstract

In this molecular docking study, the protonation states of the catalytic Asp dyad of the beta-secretase (BACE1) enzyme in the presence of eight chemically diverse inhibitors have been predicted. BACE1 catalyzes the rate-determining step in the generation of Alzheimer amyloid beta peptides and is widely considered as a promising therapeutic target. All the inhibitors were redocked into their corresponding X-ray structures using a combination of eight different protonation states of the Asp dyad for each inhibitor. Five inhibitors were primarily found to favor two different monoprotonated states, and the remaining three favor a dideprotonated state. In addition, five of them exhibited secondary preference for a diprotonated state. These results show that the knowledge of a single protonation state of the Asp dyad is not sufficient to search for the novel inhibitors of BACE1 and the most plausible state for each inhibitor must be determined prior to conducting in-silico screening.

Original languageEnglish
Pages (from-to)1275-1287
Number of pages13
JournalJournal of Chemical Information and Modeling
Volume52
Issue number5
DOIs
StatePublished - May 25 2012

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Amyloid Precursor Protein Secretases
Protonation
dyad
Amyloid beta-Peptides
Peptides
Screening
Enzymes
X rays

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

Cite this

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title = "Protonation states of the catalytic dyad of β-secretase (BACE1) in the presence of chemically diverse inhibitors: A molecular docking study",
abstract = "In this molecular docking study, the protonation states of the catalytic Asp dyad of the beta-secretase (BACE1) enzyme in the presence of eight chemically diverse inhibitors have been predicted. BACE1 catalyzes the rate-determining step in the generation of Alzheimer amyloid beta peptides and is widely considered as a promising therapeutic target. All the inhibitors were redocked into their corresponding X-ray structures using a combination of eight different protonation states of the Asp dyad for each inhibitor. Five inhibitors were primarily found to favor two different monoprotonated states, and the remaining three favor a dideprotonated state. In addition, five of them exhibited secondary preference for a diprotonated state. These results show that the knowledge of a single protonation state of the Asp dyad is not sufficient to search for the novel inhibitors of BACE1 and the most plausible state for each inhibitor must be determined prior to conducting in-silico screening.",
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AU - Prabhakar, Rajeev

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AB - In this molecular docking study, the protonation states of the catalytic Asp dyad of the beta-secretase (BACE1) enzyme in the presence of eight chemically diverse inhibitors have been predicted. BACE1 catalyzes the rate-determining step in the generation of Alzheimer amyloid beta peptides and is widely considered as a promising therapeutic target. All the inhibitors were redocked into their corresponding X-ray structures using a combination of eight different protonation states of the Asp dyad for each inhibitor. Five inhibitors were primarily found to favor two different monoprotonated states, and the remaining three favor a dideprotonated state. In addition, five of them exhibited secondary preference for a diprotonated state. These results show that the knowledge of a single protonation state of the Asp dyad is not sufficient to search for the novel inhibitors of BACE1 and the most plausible state for each inhibitor must be determined prior to conducting in-silico screening.

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