Simulation and Stability Assessment of Anti-EpCAM Immunotoxin for Cancer Therapy

Purpose: Epithelial cell adhesion molecule (EpCAM) is a dominant antigen in human colon carcinoma tissue. Topology features of this antigen are different in normal and malignant conditions; for instance, EpCAM is much less accessible to antibodies in normal cells than in cancerous tissues. Hence, Ep...

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Autores principales: Hosseinian, Seyed-Ali, Haddad-Mashadrizeh, Aliakbar, Dolatabadi, Samaneh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Tabriz University of Medical Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156485/
https://www.ncbi.nlm.nih.gov/pubmed/30276141
http://dx.doi.org/10.15171/apb.2018.052
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author Hosseinian, Seyed-Ali
Haddad-Mashadrizeh, Aliakbar
Dolatabadi, Samaneh
author_facet Hosseinian, Seyed-Ali
Haddad-Mashadrizeh, Aliakbar
Dolatabadi, Samaneh
author_sort Hosseinian, Seyed-Ali
collection PubMed
description Purpose: Epithelial cell adhesion molecule (EpCAM) is a dominant antigen in human colon carcinoma tissue. Topology features of this antigen are different in normal and malignant conditions; for instance, EpCAM is much less accessible to antibodies in normal cells than in cancerous tissues. Hence, EpCAM has been considered as a suitable candidate for cancer target therapy via immunotoxins (ITs) development. In this study, attention was focused on the stability assessment of anti-EpCAM-IT (anti-Ep-IT) to design a novel IT. Methods: The 3D structures of the antibody template and the toxin segment of anti-Ep-IT were retrieved from PDB. Discovery Studio3.0 was used to separate the ligands and water molecules. The antibody (Ab) fragment of anti-Ep-IT was aligned using protein blast (BLAST-p), and SWISS-MODEL database was used for Ab modeling. IT modeling was accomplished using MODELLER 9.15. Also, GROMACS 5.07 was used for molecular dynamic (MD) simulation step. Moreover, ERRAT and RAMPAGE databases were used for quality assessment of the structures. Results: BLAST-p results indicated that antibody moiety of IT has the highest E-value and query coverage scores to the monoclonal antibody (mAb) 4D5MOC-B. Modeling by SWISS-MODEL provided a reasonable template for Ab portion compared to MODELLER. The best modeled full-length IT with the lowest RMSD values was selected. Finally, RMSD plot for MD stage demonstrated constant values from 7000ps to 20000ps. Conclusion: In general, both modeling results and their quality evaluations were satisfactory for designing IT. Moreover, RMSD plot revealed that IT stability was preserved during the simulation. Overall, our findings led to modeling and simulation of the anti-Ep-IT with more structural stability.
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spelling pubmed-61564852018-10-01 Simulation and Stability Assessment of Anti-EpCAM Immunotoxin for Cancer Therapy Hosseinian, Seyed-Ali Haddad-Mashadrizeh, Aliakbar Dolatabadi, Samaneh Adv Pharm Bull Research Article Purpose: Epithelial cell adhesion molecule (EpCAM) is a dominant antigen in human colon carcinoma tissue. Topology features of this antigen are different in normal and malignant conditions; for instance, EpCAM is much less accessible to antibodies in normal cells than in cancerous tissues. Hence, EpCAM has been considered as a suitable candidate for cancer target therapy via immunotoxins (ITs) development. In this study, attention was focused on the stability assessment of anti-EpCAM-IT (anti-Ep-IT) to design a novel IT. Methods: The 3D structures of the antibody template and the toxin segment of anti-Ep-IT were retrieved from PDB. Discovery Studio3.0 was used to separate the ligands and water molecules. The antibody (Ab) fragment of anti-Ep-IT was aligned using protein blast (BLAST-p), and SWISS-MODEL database was used for Ab modeling. IT modeling was accomplished using MODELLER 9.15. Also, GROMACS 5.07 was used for molecular dynamic (MD) simulation step. Moreover, ERRAT and RAMPAGE databases were used for quality assessment of the structures. Results: BLAST-p results indicated that antibody moiety of IT has the highest E-value and query coverage scores to the monoclonal antibody (mAb) 4D5MOC-B. Modeling by SWISS-MODEL provided a reasonable template for Ab portion compared to MODELLER. The best modeled full-length IT with the lowest RMSD values was selected. Finally, RMSD plot for MD stage demonstrated constant values from 7000ps to 20000ps. Conclusion: In general, both modeling results and their quality evaluations were satisfactory for designing IT. Moreover, RMSD plot revealed that IT stability was preserved during the simulation. Overall, our findings led to modeling and simulation of the anti-Ep-IT with more structural stability. Tabriz University of Medical Sciences 2018-08 2018-08-29 /pmc/articles/PMC6156485/ /pubmed/30276141 http://dx.doi.org/10.15171/apb.2018.052 Text en ©2018 The Authors. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, as long as the original authors and source are cited. No permission is required from the authors or the publishers.
spellingShingle Research Article
Hosseinian, Seyed-Ali
Haddad-Mashadrizeh, Aliakbar
Dolatabadi, Samaneh
Simulation and Stability Assessment of Anti-EpCAM Immunotoxin for Cancer Therapy
title Simulation and Stability Assessment of Anti-EpCAM Immunotoxin for Cancer Therapy
title_full Simulation and Stability Assessment of Anti-EpCAM Immunotoxin for Cancer Therapy
title_fullStr Simulation and Stability Assessment of Anti-EpCAM Immunotoxin for Cancer Therapy
title_full_unstemmed Simulation and Stability Assessment of Anti-EpCAM Immunotoxin for Cancer Therapy
title_short Simulation and Stability Assessment of Anti-EpCAM Immunotoxin for Cancer Therapy
title_sort simulation and stability assessment of anti-epcam immunotoxin for cancer therapy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156485/
https://www.ncbi.nlm.nih.gov/pubmed/30276141
http://dx.doi.org/10.15171/apb.2018.052
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