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Lipid Composition Is Critical for Accurate Membrane Permeability Prediction of Cyclic Peptides by Molecular Dynamics Simulations

[Image: see text] Cyclic peptides have attracted attention as a promising pharmaceutical modality due to their potential to selectively inhibit previously undruggable targets, such as intracellular protein–protein interactions. Poor membrane permeability is the biggest bottleneck hindering successfu...

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Autores principales: Sugita, Masatake, Fujie, Takuya, Yanagisawa, Keisuke, Ohue, Masahito, Akiyama, Yutaka
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9516681/
https://www.ncbi.nlm.nih.gov/pubmed/36053061
http://dx.doi.org/10.1021/acs.jcim.2c00931
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author Sugita, Masatake
Fujie, Takuya
Yanagisawa, Keisuke
Ohue, Masahito
Akiyama, Yutaka
author_facet Sugita, Masatake
Fujie, Takuya
Yanagisawa, Keisuke
Ohue, Masahito
Akiyama, Yutaka
author_sort Sugita, Masatake
collection PubMed
description [Image: see text] Cyclic peptides have attracted attention as a promising pharmaceutical modality due to their potential to selectively inhibit previously undruggable targets, such as intracellular protein–protein interactions. Poor membrane permeability is the biggest bottleneck hindering successful drug discovery based on cyclic peptides. Therefore, the development of computational methods that can predict membrane permeability and support elucidation of the membrane permeation mechanism of drug candidate peptides is much sought after. In this study, we developed a protocol to simulate the behavior in membrane permeation steps and estimate the membrane permeability of large cyclic peptides with more than or equal to 10 residues. This protocol requires the use of a more realistic membrane model than a single-lipid phospholipid bilayer. To select a membrane model, we first analyzed the effect of cholesterol concentration in the model membrane on the potential of mean force and hydrogen bonding networks along the direction perpendicular to the membrane surface as predicted by molecular dynamics simulations using cyclosporine A. These results suggest that a membrane model with 40 or 50 mol % cholesterol was suitable for predicting the permeation process. Subsequently, two types of membrane models containing 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and 40 and 50 mol % cholesterol were used. To validate the efficiency of our protocol, the membrane permeability of 18 ten-residue peptides was predicted. Correlation coefficients of R > 0.8 between the experimental and calculated permeability values were obtained with both model membranes. The results of this study demonstrate that the lipid membrane is not just a medium but also among the main factors determining the membrane permeability of molecules. The computational protocol proposed in this study and the findings obtained on the effect of membrane model composition will contribute to building a schematic view of the membrane permeation process. Furthermore, the results of this study will eventually aid the elucidation of design rules for peptide drugs with high membrane permeability.
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spelling pubmed-95166812022-09-29 Lipid Composition Is Critical for Accurate Membrane Permeability Prediction of Cyclic Peptides by Molecular Dynamics Simulations Sugita, Masatake Fujie, Takuya Yanagisawa, Keisuke Ohue, Masahito Akiyama, Yutaka J Chem Inf Model [Image: see text] Cyclic peptides have attracted attention as a promising pharmaceutical modality due to their potential to selectively inhibit previously undruggable targets, such as intracellular protein–protein interactions. Poor membrane permeability is the biggest bottleneck hindering successful drug discovery based on cyclic peptides. Therefore, the development of computational methods that can predict membrane permeability and support elucidation of the membrane permeation mechanism of drug candidate peptides is much sought after. In this study, we developed a protocol to simulate the behavior in membrane permeation steps and estimate the membrane permeability of large cyclic peptides with more than or equal to 10 residues. This protocol requires the use of a more realistic membrane model than a single-lipid phospholipid bilayer. To select a membrane model, we first analyzed the effect of cholesterol concentration in the model membrane on the potential of mean force and hydrogen bonding networks along the direction perpendicular to the membrane surface as predicted by molecular dynamics simulations using cyclosporine A. These results suggest that a membrane model with 40 or 50 mol % cholesterol was suitable for predicting the permeation process. Subsequently, two types of membrane models containing 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and 40 and 50 mol % cholesterol were used. To validate the efficiency of our protocol, the membrane permeability of 18 ten-residue peptides was predicted. Correlation coefficients of R > 0.8 between the experimental and calculated permeability values were obtained with both model membranes. The results of this study demonstrate that the lipid membrane is not just a medium but also among the main factors determining the membrane permeability of molecules. The computational protocol proposed in this study and the findings obtained on the effect of membrane model composition will contribute to building a schematic view of the membrane permeation process. Furthermore, the results of this study will eventually aid the elucidation of design rules for peptide drugs with high membrane permeability. American Chemical Society 2022-09-02 2022-09-26 /pmc/articles/PMC9516681/ /pubmed/36053061 http://dx.doi.org/10.1021/acs.jcim.2c00931 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Sugita, Masatake
Fujie, Takuya
Yanagisawa, Keisuke
Ohue, Masahito
Akiyama, Yutaka
Lipid Composition Is Critical for Accurate Membrane Permeability Prediction of Cyclic Peptides by Molecular Dynamics Simulations
title Lipid Composition Is Critical for Accurate Membrane Permeability Prediction of Cyclic Peptides by Molecular Dynamics Simulations
title_full Lipid Composition Is Critical for Accurate Membrane Permeability Prediction of Cyclic Peptides by Molecular Dynamics Simulations
title_fullStr Lipid Composition Is Critical for Accurate Membrane Permeability Prediction of Cyclic Peptides by Molecular Dynamics Simulations
title_full_unstemmed Lipid Composition Is Critical for Accurate Membrane Permeability Prediction of Cyclic Peptides by Molecular Dynamics Simulations
title_short Lipid Composition Is Critical for Accurate Membrane Permeability Prediction of Cyclic Peptides by Molecular Dynamics Simulations
title_sort lipid composition is critical for accurate membrane permeability prediction of cyclic peptides by molecular dynamics simulations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9516681/
https://www.ncbi.nlm.nih.gov/pubmed/36053061
http://dx.doi.org/10.1021/acs.jcim.2c00931
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