Computer-aided peptide-based drug design for inositol-requiring enzyme 1
Inositol-requiring enzyme 1 (IRE1), an endoplasmic reticulum (ER) transmembrane protein with both kinase and endoribonuclease activities, plays an essential role during ER stress and its subsequent unfolded protein response (UPR). Recent evidence shows IRE1 signaling contributes to tumorigenesis an...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Tehran University of Medical Sciences
2023-10-01
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| Series: | Basic & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://bccr.tums.ac.ir/index.php/bccrj/article/view/495 |
| _version_ | 1797394732219891712 |
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| author | Alireza Ghanbari Amir Norouzy Negar Balmeh Najaf Allahyari Fard Mohammad Amin Moosavi |
| author_facet | Alireza Ghanbari Amir Norouzy Negar Balmeh Najaf Allahyari Fard Mohammad Amin Moosavi |
| author_sort | Alireza Ghanbari |
| collection | DOAJ |
| description |
Inositol-requiring enzyme 1 (IRE1), an endoplasmic reticulum (ER) transmembrane
protein with both kinase and endoribonuclease activities, plays an essential role during
ER stress and its subsequent unfolded protein response (UPR). Recent evidence shows
IRE1 signaling contributes to tumorigenesis and cancer progression, pointing to the
therapeutic importance of this conserved arm of the UPR. Here, we employed different
computational tools to design and predict short peptides with the capability of disrupting IRE1 dimerization/oligomerization, as a strategy for inhibiting its Kinase and
RNase activities. A mutation-based peptide library was constructed using mCSM-PPI2
and OSPREY 3.0. The molecular interaction analyses between the designed peptides
and IRE1 protein were conducted using the HADDOCK 2.2 online server, followed
with molecular dynamics analysis by the GROMACS 2020 package. We then selected
short peptide candidates that exhibited high affinity and best predicted physicochemical properties in complex with IRE1. Finally, online servers, such as ToxinPred and
AllerTop, were used to identify the best peptide candidates that showed no significant
allergenic or cytotoxic properties. These rational designed peptides with the capability
of binding to IRE1 oligomerization domain can be considered as potential drug candidates for disrupting IRE1 activity in cancer and related diseases, pending for further
validation by in silico and experimental studies.
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| first_indexed | 2024-03-09T00:24:26Z |
| format | Article |
| id | doaj.art-8db4427a16f14047b99b77f4fc237956 |
| institution | Directory Open Access Journal |
| issn | 2228-6527 2228-5466 |
| language | English |
| last_indexed | 2024-03-09T00:24:26Z |
| publishDate | 2023-10-01 |
| publisher | Tehran University of Medical Sciences |
| record_format | Article |
| series | Basic & Clinical Cancer Research |
| spelling | doaj.art-8db4427a16f14047b99b77f4fc2379562023-12-12T04:38:24ZengTehran University of Medical SciencesBasic & Clinical Cancer Research2228-65272228-54662023-10-01144Computer-aided peptide-based drug design for inositol-requiring enzyme 1Alireza Ghanbari0Amir Norouzy1Negar Balmeh2Najaf Allahyari Fard3Mohammad Amin Moosavi4NIGEBNIGEBNIGEBNIGEBNIGEB Inositol-requiring enzyme 1 (IRE1), an endoplasmic reticulum (ER) transmembrane protein with both kinase and endoribonuclease activities, plays an essential role during ER stress and its subsequent unfolded protein response (UPR). Recent evidence shows IRE1 signaling contributes to tumorigenesis and cancer progression, pointing to the therapeutic importance of this conserved arm of the UPR. Here, we employed different computational tools to design and predict short peptides with the capability of disrupting IRE1 dimerization/oligomerization, as a strategy for inhibiting its Kinase and RNase activities. A mutation-based peptide library was constructed using mCSM-PPI2 and OSPREY 3.0. The molecular interaction analyses between the designed peptides and IRE1 protein were conducted using the HADDOCK 2.2 online server, followed with molecular dynamics analysis by the GROMACS 2020 package. We then selected short peptide candidates that exhibited high affinity and best predicted physicochemical properties in complex with IRE1. Finally, online servers, such as ToxinPred and AllerTop, were used to identify the best peptide candidates that showed no significant allergenic or cytotoxic properties. These rational designed peptides with the capability of binding to IRE1 oligomerization domain can be considered as potential drug candidates for disrupting IRE1 activity in cancer and related diseases, pending for further validation by in silico and experimental studies. https://bccr.tums.ac.ir/index.php/bccrj/article/view/495Bioinformaticscancerdrug designinositol-requiring enzyme 1short peptides |
| spellingShingle | Alireza Ghanbari Amir Norouzy Negar Balmeh Najaf Allahyari Fard Mohammad Amin Moosavi Computer-aided peptide-based drug design for inositol-requiring enzyme 1 Basic & Clinical Cancer Research Bioinformatics cancer drug design inositol-requiring enzyme 1 short peptides |
| title | Computer-aided peptide-based drug design for inositol-requiring enzyme 1 |
| title_full | Computer-aided peptide-based drug design for inositol-requiring enzyme 1 |
| title_fullStr | Computer-aided peptide-based drug design for inositol-requiring enzyme 1 |
| title_full_unstemmed | Computer-aided peptide-based drug design for inositol-requiring enzyme 1 |
| title_short | Computer-aided peptide-based drug design for inositol-requiring enzyme 1 |
| title_sort | computer aided peptide based drug design for inositol requiring enzyme 1 |
| topic | Bioinformatics cancer drug design inositol-requiring enzyme 1 short peptides |
| url | https://bccr.tums.ac.ir/index.php/bccrj/article/view/495 |
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