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Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis
Cyclophilin D (CypD) is a mitochondrial matrix peptidyl prolidase that regulates the mitochondrial permeability transition pore. Inhibition of CypD was suggested as a therapeutic strategy for acute pancreatitis. Peptide inhibitors emerged as novel binding ligand for blocking receptor activity. In th...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10695616/ http://dx.doi.org/10.1097/MD.0000000000036188 |
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author | Li, Yuehong Liu, Ting Lai, Xiaoyan Xie, Huifang Tang, Heng Wu, Shuangchan Li, Yongshun |
author_facet | Li, Yuehong Liu, Ting Lai, Xiaoyan Xie, Huifang Tang, Heng Wu, Shuangchan Li, Yongshun |
author_sort | Li, Yuehong |
collection | PubMed |
description | Cyclophilin D (CypD) is a mitochondrial matrix peptidyl prolidase that regulates the mitochondrial permeability transition pore. Inhibition of CypD was suggested as a therapeutic strategy for acute pancreatitis. Peptide inhibitors emerged as novel binding ligand for blocking receptor activity. In this study, we present our computational approach for designing peptide inhibitors of CypD. The 3-D structure of random peptides were built, and docked into the active center of CypD using Rosetta script integrated FlexPepDock module. The peptide displayed the lowest binding energy against CypD was further selected for virtual iterative mutation based on virtual mutagenesis and molecular docking. Finally, the top 5 peptides with the lowest binding energy was selected for validating their affinity against CypD using inhibitory assay. We showed 4 out of the selected 5 peptides were capable for blocking the activity of CypD, while WACLQ display the strongest affinity against CypD, which reached 0.28 mM. The binding mechanism between WACLQ and CypD was characterized using molecular dynamics simulation. Here, we proved our approach can be a robust method for screening peptide inhibitors. |
format | Online Article Text |
id | pubmed-10695616 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-106956162023-12-05 Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis Li, Yuehong Liu, Ting Lai, Xiaoyan Xie, Huifang Tang, Heng Wu, Shuangchan Li, Yongshun Medicine (Baltimore) 3800 Cyclophilin D (CypD) is a mitochondrial matrix peptidyl prolidase that regulates the mitochondrial permeability transition pore. Inhibition of CypD was suggested as a therapeutic strategy for acute pancreatitis. Peptide inhibitors emerged as novel binding ligand for blocking receptor activity. In this study, we present our computational approach for designing peptide inhibitors of CypD. The 3-D structure of random peptides were built, and docked into the active center of CypD using Rosetta script integrated FlexPepDock module. The peptide displayed the lowest binding energy against CypD was further selected for virtual iterative mutation based on virtual mutagenesis and molecular docking. Finally, the top 5 peptides with the lowest binding energy was selected for validating their affinity against CypD using inhibitory assay. We showed 4 out of the selected 5 peptides were capable for blocking the activity of CypD, while WACLQ display the strongest affinity against CypD, which reached 0.28 mM. The binding mechanism between WACLQ and CypD was characterized using molecular dynamics simulation. Here, we proved our approach can be a robust method for screening peptide inhibitors. Lippincott Williams & Wilkins 2023-12-01 /pmc/articles/PMC10695616/ http://dx.doi.org/10.1097/MD.0000000000036188 Text en Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY) (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | 3800 Li, Yuehong Liu, Ting Lai, Xiaoyan Xie, Huifang Tang, Heng Wu, Shuangchan Li, Yongshun Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis |
title | Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis |
title_full | Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis |
title_fullStr | Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis |
title_full_unstemmed | Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis |
title_short | Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis |
title_sort | rational design peptide inhibitors of cyclophilin d as a potential treatment for acute pancreatitis |
topic | 3800 |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10695616/ http://dx.doi.org/10.1097/MD.0000000000036188 |
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