Cargando…

2D, 3D-QSAR study and docking of vascular endothelial growth factor receptor 3 (VEGFR3) inhibitors for potential treatment of retinoblastoma

Background: Retinoblastoma is currently the most common malignant tumor seen in newborns and children’s eyes worldwide, posing a life-threatening hazard. Chemotherapy is an integral part of retinoblastoma treatment. However, the chemotherapeutic agents used in clinics often lead to drug resistance....

Descripción completa

Detalles Bibliográficos
Autores principales: Ren, Rui, Gao, Liyu, Li, Guoqi, Wang, Shuqiang, Zhao, Yangzhong, Wang, Haitong, Liu, Jianwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10119426/
https://www.ncbi.nlm.nih.gov/pubmed/37089961
http://dx.doi.org/10.3389/fphar.2023.1177282
_version_ 1785029019612217344
author Ren, Rui
Gao, Liyu
Li, Guoqi
Wang, Shuqiang
Zhao, Yangzhong
Wang, Haitong
Liu, Jianwei
author_facet Ren, Rui
Gao, Liyu
Li, Guoqi
Wang, Shuqiang
Zhao, Yangzhong
Wang, Haitong
Liu, Jianwei
author_sort Ren, Rui
collection PubMed
description Background: Retinoblastoma is currently the most common malignant tumor seen in newborns and children’s eyes worldwide, posing a life-threatening hazard. Chemotherapy is an integral part of retinoblastoma treatment. However, the chemotherapeutic agents used in clinics often lead to drug resistance. Thus there is a need to investigate new chemotherapy-targeted agents. VEGFR3 inhibitors are anti-tumour-growth and could be used to develop novel retinoblastoma-targeted agents. Objective: To predict drug activity, discover influencing factors and design new drugs by building 2D, 3D-QSAR models. Method: First, linear and non-linear QSAR models were built using heuristic methods and gene expression programming (GEP). The comparative molecular similarity indices analysis (COMISA) was then used to construct 3D-QSAR models through the SYBYL software. New drugs were designed by changing drug activity factors in both models, and molecular docking experiments were performed. Result: The best linear model created using HM had an R(2), S(2), and R(2)cv of 0.82, 0.02, and 0.77, respectively. For the training and test sets, the best non-linear model created using GEP had correlation coefficients of 0.83 and 0.72 with mean errors of 0.02 and 0.04. The 3D model designed using SYBYL passed external validation due to its high Q(2) (0.503), R(2) (0.805), and F-value (76.52), as well as its low standard error of SEE value (0.172). This demonstrates the model’s reliability and excellent predictive ability. Based on the molecular descriptors of the 2D model and the contour plots of the 3D model, we designed 100 new compounds using the best active compound 14 as a template. We performed activity prediction and molecular docking experiments on them, in which compound 14.d performed best regarding combined drug activity and docking ability. Conclusion: The non-linear model created using GEP was more stable and had a more substantial predictive power than the linear model built using the heuristic technique (HM). The compound 14.d designed in this experiment has the potential for anti-retinoblastoma treatment, which provides new design ideas and directions for retinoblastoma-targeted drugs.
format Online
Article
Text
id pubmed-10119426
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-101194262023-04-22 2D, 3D-QSAR study and docking of vascular endothelial growth factor receptor 3 (VEGFR3) inhibitors for potential treatment of retinoblastoma Ren, Rui Gao, Liyu Li, Guoqi Wang, Shuqiang Zhao, Yangzhong Wang, Haitong Liu, Jianwei Front Pharmacol Pharmacology Background: Retinoblastoma is currently the most common malignant tumor seen in newborns and children’s eyes worldwide, posing a life-threatening hazard. Chemotherapy is an integral part of retinoblastoma treatment. However, the chemotherapeutic agents used in clinics often lead to drug resistance. Thus there is a need to investigate new chemotherapy-targeted agents. VEGFR3 inhibitors are anti-tumour-growth and could be used to develop novel retinoblastoma-targeted agents. Objective: To predict drug activity, discover influencing factors and design new drugs by building 2D, 3D-QSAR models. Method: First, linear and non-linear QSAR models were built using heuristic methods and gene expression programming (GEP). The comparative molecular similarity indices analysis (COMISA) was then used to construct 3D-QSAR models through the SYBYL software. New drugs were designed by changing drug activity factors in both models, and molecular docking experiments were performed. Result: The best linear model created using HM had an R(2), S(2), and R(2)cv of 0.82, 0.02, and 0.77, respectively. For the training and test sets, the best non-linear model created using GEP had correlation coefficients of 0.83 and 0.72 with mean errors of 0.02 and 0.04. The 3D model designed using SYBYL passed external validation due to its high Q(2) (0.503), R(2) (0.805), and F-value (76.52), as well as its low standard error of SEE value (0.172). This demonstrates the model’s reliability and excellent predictive ability. Based on the molecular descriptors of the 2D model and the contour plots of the 3D model, we designed 100 new compounds using the best active compound 14 as a template. We performed activity prediction and molecular docking experiments on them, in which compound 14.d performed best regarding combined drug activity and docking ability. Conclusion: The non-linear model created using GEP was more stable and had a more substantial predictive power than the linear model built using the heuristic technique (HM). The compound 14.d designed in this experiment has the potential for anti-retinoblastoma treatment, which provides new design ideas and directions for retinoblastoma-targeted drugs. Frontiers Media S.A. 2023-04-07 /pmc/articles/PMC10119426/ /pubmed/37089961 http://dx.doi.org/10.3389/fphar.2023.1177282 Text en Copyright © 2023 Ren, Gao, Li, Wang, Zhao, Wang and Liu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Ren, Rui
Gao, Liyu
Li, Guoqi
Wang, Shuqiang
Zhao, Yangzhong
Wang, Haitong
Liu, Jianwei
2D, 3D-QSAR study and docking of vascular endothelial growth factor receptor 3 (VEGFR3) inhibitors for potential treatment of retinoblastoma
title 2D, 3D-QSAR study and docking of vascular endothelial growth factor receptor 3 (VEGFR3) inhibitors for potential treatment of retinoblastoma
title_full 2D, 3D-QSAR study and docking of vascular endothelial growth factor receptor 3 (VEGFR3) inhibitors for potential treatment of retinoblastoma
title_fullStr 2D, 3D-QSAR study and docking of vascular endothelial growth factor receptor 3 (VEGFR3) inhibitors for potential treatment of retinoblastoma
title_full_unstemmed 2D, 3D-QSAR study and docking of vascular endothelial growth factor receptor 3 (VEGFR3) inhibitors for potential treatment of retinoblastoma
title_short 2D, 3D-QSAR study and docking of vascular endothelial growth factor receptor 3 (VEGFR3) inhibitors for potential treatment of retinoblastoma
title_sort 2d, 3d-qsar study and docking of vascular endothelial growth factor receptor 3 (vegfr3) inhibitors for potential treatment of retinoblastoma
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10119426/
https://www.ncbi.nlm.nih.gov/pubmed/37089961
http://dx.doi.org/10.3389/fphar.2023.1177282
work_keys_str_mv AT renrui 2d3dqsarstudyanddockingofvascularendothelialgrowthfactorreceptor3vegfr3inhibitorsforpotentialtreatmentofretinoblastoma
AT gaoliyu 2d3dqsarstudyanddockingofvascularendothelialgrowthfactorreceptor3vegfr3inhibitorsforpotentialtreatmentofretinoblastoma
AT liguoqi 2d3dqsarstudyanddockingofvascularendothelialgrowthfactorreceptor3vegfr3inhibitorsforpotentialtreatmentofretinoblastoma
AT wangshuqiang 2d3dqsarstudyanddockingofvascularendothelialgrowthfactorreceptor3vegfr3inhibitorsforpotentialtreatmentofretinoblastoma
AT zhaoyangzhong 2d3dqsarstudyanddockingofvascularendothelialgrowthfactorreceptor3vegfr3inhibitorsforpotentialtreatmentofretinoblastoma
AT wanghaitong 2d3dqsarstudyanddockingofvascularendothelialgrowthfactorreceptor3vegfr3inhibitorsforpotentialtreatmentofretinoblastoma
AT liujianwei 2d3dqsarstudyanddockingofvascularendothelialgrowthfactorreceptor3vegfr3inhibitorsforpotentialtreatmentofretinoblastoma