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Probing the Mechanisms of Inhibitors Binding to Presenilin Homologue Using Molecular Dynamics Simulations

γ-secretase is an intramembrane proteolytic enzyme that is mainly involved in the cleavage and hydrolysis of the amyloid precursor (APP). The catalytic subunit presenilin 1 (PS1) is the catalytic subunit of γ-secretase. Since it was found that PS1 is responsible for Aβ-producing proteolytic activity...

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Autores principales: Wang, Min, Liu, Kaifeng, Ma, Yingying, Han, Weiwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10004098/
https://www.ncbi.nlm.nih.gov/pubmed/36903320
http://dx.doi.org/10.3390/molecules28052076
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author Wang, Min
Liu, Kaifeng
Ma, Yingying
Han, Weiwei
author_facet Wang, Min
Liu, Kaifeng
Ma, Yingying
Han, Weiwei
author_sort Wang, Min
collection PubMed
description γ-secretase is an intramembrane proteolytic enzyme that is mainly involved in the cleavage and hydrolysis of the amyloid precursor (APP). The catalytic subunit presenilin 1 (PS1) is the catalytic subunit of γ-secretase. Since it was found that PS1 is responsible for Aβ-producing proteolytic activity, which is involved in Alzheimer’s disease, it is believed that reducing the activity of PS1 and preventing or delaying the production of Aβ could help treat Alzheimer’s disease. Consequently, in recent years, researchers have begun investigating the potential clinical efficacy of PS1 inhibitors. Currently, most PS1 inhibitors are only used as a tool to study the structure and function of PS1, and a few inhibitors with a high selectivity have been tested in clinics. Less-selective PS1 inhibitors were found to not only inhibit Aβ production but also inhibit Notch cleavage, which led to serious adverse events. The archaeal presenilin homologue (PSH) is a surrogate protease of presenilin that is useful for agent screening. In this study, we performed 200 ns molecular dynamics simulations (MD) of four systems to explore the conformational changes of different ligands binding to PSH. Our results indicated that the PSH-L679 system formed 3–10 helices in TM4, loosening up TM4 and allowing substrates to enter the catalytic pocket, thereby making it less inhibitory. Additionally, we found that III-31-C can bring TM4 and TM6 closer, resulting in the contraction of the PSH active pocket. Altogether, these results provide the basis for the potential design of newer PS1 inhibitors.
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spelling pubmed-100040982023-03-11 Probing the Mechanisms of Inhibitors Binding to Presenilin Homologue Using Molecular Dynamics Simulations Wang, Min Liu, Kaifeng Ma, Yingying Han, Weiwei Molecules Article γ-secretase is an intramembrane proteolytic enzyme that is mainly involved in the cleavage and hydrolysis of the amyloid precursor (APP). The catalytic subunit presenilin 1 (PS1) is the catalytic subunit of γ-secretase. Since it was found that PS1 is responsible for Aβ-producing proteolytic activity, which is involved in Alzheimer’s disease, it is believed that reducing the activity of PS1 and preventing or delaying the production of Aβ could help treat Alzheimer’s disease. Consequently, in recent years, researchers have begun investigating the potential clinical efficacy of PS1 inhibitors. Currently, most PS1 inhibitors are only used as a tool to study the structure and function of PS1, and a few inhibitors with a high selectivity have been tested in clinics. Less-selective PS1 inhibitors were found to not only inhibit Aβ production but also inhibit Notch cleavage, which led to serious adverse events. The archaeal presenilin homologue (PSH) is a surrogate protease of presenilin that is useful for agent screening. In this study, we performed 200 ns molecular dynamics simulations (MD) of four systems to explore the conformational changes of different ligands binding to PSH. Our results indicated that the PSH-L679 system formed 3–10 helices in TM4, loosening up TM4 and allowing substrates to enter the catalytic pocket, thereby making it less inhibitory. Additionally, we found that III-31-C can bring TM4 and TM6 closer, resulting in the contraction of the PSH active pocket. Altogether, these results provide the basis for the potential design of newer PS1 inhibitors. MDPI 2023-02-22 /pmc/articles/PMC10004098/ /pubmed/36903320 http://dx.doi.org/10.3390/molecules28052076 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Min
Liu, Kaifeng
Ma, Yingying
Han, Weiwei
Probing the Mechanisms of Inhibitors Binding to Presenilin Homologue Using Molecular Dynamics Simulations
title Probing the Mechanisms of Inhibitors Binding to Presenilin Homologue Using Molecular Dynamics Simulations
title_full Probing the Mechanisms of Inhibitors Binding to Presenilin Homologue Using Molecular Dynamics Simulations
title_fullStr Probing the Mechanisms of Inhibitors Binding to Presenilin Homologue Using Molecular Dynamics Simulations
title_full_unstemmed Probing the Mechanisms of Inhibitors Binding to Presenilin Homologue Using Molecular Dynamics Simulations
title_short Probing the Mechanisms of Inhibitors Binding to Presenilin Homologue Using Molecular Dynamics Simulations
title_sort probing the mechanisms of inhibitors binding to presenilin homologue using molecular dynamics simulations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10004098/
https://www.ncbi.nlm.nih.gov/pubmed/36903320
http://dx.doi.org/10.3390/molecules28052076
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