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Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B-Raf(V600E)/KDR Inhibitors Using Docking and 3D-QSAR Approaches

Research and development of multi-target inhibitors has attracted increasing attention as anticancer therapeutics. B-Raf(V600E) synergistically works with vascular endothelial growth factor receptor 2 (KDR) to promote the occurrence and progression of cancers, and the development of dual-target drug...

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Autores principales: Liu, Hai-Chun, Tang, San-Zhi, Lu, Shuai, Ran, Ting, Wang, Jian, Zhang, Yan-Min, Xu, An-Yang, Lu, Tao, Chen, Ya-Dong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632759/
https://www.ncbi.nlm.nih.gov/pubmed/26501259
http://dx.doi.org/10.3390/ijms161024451
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author Liu, Hai-Chun
Tang, San-Zhi
Lu, Shuai
Ran, Ting
Wang, Jian
Zhang, Yan-Min
Xu, An-Yang
Lu, Tao
Chen, Ya-Dong
author_facet Liu, Hai-Chun
Tang, San-Zhi
Lu, Shuai
Ran, Ting
Wang, Jian
Zhang, Yan-Min
Xu, An-Yang
Lu, Tao
Chen, Ya-Dong
author_sort Liu, Hai-Chun
collection PubMed
description Research and development of multi-target inhibitors has attracted increasing attention as anticancer therapeutics. B-Raf(V600E) synergistically works with vascular endothelial growth factor receptor 2 (KDR) to promote the occurrence and progression of cancers, and the development of dual-target drugs simultaneously against these two kinds of kinase may offer a better treatment advantage. In this paper, docking and three-dimensional quantitative structure activity relationship (3D-QSAR) studies were performed on a series of dual B-Raf/KDR inhibitors with a novel hinge-binding group, [5,6]-fused bicyclic scaffold. Docking studies revealed optimal binding conformations of these compounds interacting with both B-Raf and KDR. Based on these conformations, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models were constructed, and the best CoMFA (q(2) = 0.542, r(2) = 0.989 for B-Raf; q(2) = 0.768, r(2) = 0.991 for KDR) and CoMSIA models (q(2) = 0.519, r(2) = 0.992 for B-Raf; q(2) = 0.849, r(2) = 0.993 for KDR) were generated. Further external validations confirmed their predictability, yielding satisfactory correlation coefficients (r(2)(pred) = 0.764 (CoMFA), r(2)(pred) = 0.841 (CoMSIA) for B-Raf, r(2)(pred) = 0.912 (CoMFA), r(2)(pred) = 0.846 (CoMSIA) for KDR, respectively). Through graphical analysis and comparison on docking results and 3D-QSAR contour maps, key amino acids that affect the ligand-receptor interactions were identified and structural features influencing the activities were discussed. New potent derivatives were designed, and subjected to preliminary pharmacological evaluation. The study may offer useful references for the modification and development of novel dual B-Raf/KDR inhibitors.
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spelling pubmed-46327592015-11-23 Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B-Raf(V600E)/KDR Inhibitors Using Docking and 3D-QSAR Approaches Liu, Hai-Chun Tang, San-Zhi Lu, Shuai Ran, Ting Wang, Jian Zhang, Yan-Min Xu, An-Yang Lu, Tao Chen, Ya-Dong Int J Mol Sci Article Research and development of multi-target inhibitors has attracted increasing attention as anticancer therapeutics. B-Raf(V600E) synergistically works with vascular endothelial growth factor receptor 2 (KDR) to promote the occurrence and progression of cancers, and the development of dual-target drugs simultaneously against these two kinds of kinase may offer a better treatment advantage. In this paper, docking and three-dimensional quantitative structure activity relationship (3D-QSAR) studies were performed on a series of dual B-Raf/KDR inhibitors with a novel hinge-binding group, [5,6]-fused bicyclic scaffold. Docking studies revealed optimal binding conformations of these compounds interacting with both B-Raf and KDR. Based on these conformations, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models were constructed, and the best CoMFA (q(2) = 0.542, r(2) = 0.989 for B-Raf; q(2) = 0.768, r(2) = 0.991 for KDR) and CoMSIA models (q(2) = 0.519, r(2) = 0.992 for B-Raf; q(2) = 0.849, r(2) = 0.993 for KDR) were generated. Further external validations confirmed their predictability, yielding satisfactory correlation coefficients (r(2)(pred) = 0.764 (CoMFA), r(2)(pred) = 0.841 (CoMSIA) for B-Raf, r(2)(pred) = 0.912 (CoMFA), r(2)(pred) = 0.846 (CoMSIA) for KDR, respectively). Through graphical analysis and comparison on docking results and 3D-QSAR contour maps, key amino acids that affect the ligand-receptor interactions were identified and structural features influencing the activities were discussed. New potent derivatives were designed, and subjected to preliminary pharmacological evaluation. The study may offer useful references for the modification and development of novel dual B-Raf/KDR inhibitors. MDPI 2015-10-15 /pmc/articles/PMC4632759/ /pubmed/26501259 http://dx.doi.org/10.3390/ijms161024451 Text en © 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Liu, Hai-Chun
Tang, San-Zhi
Lu, Shuai
Ran, Ting
Wang, Jian
Zhang, Yan-Min
Xu, An-Yang
Lu, Tao
Chen, Ya-Dong
Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B-Raf(V600E)/KDR Inhibitors Using Docking and 3D-QSAR Approaches
title Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B-Raf(V600E)/KDR Inhibitors Using Docking and 3D-QSAR Approaches
title_full Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B-Raf(V600E)/KDR Inhibitors Using Docking and 3D-QSAR Approaches
title_fullStr Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B-Raf(V600E)/KDR Inhibitors Using Docking and 3D-QSAR Approaches
title_full_unstemmed Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B-Raf(V600E)/KDR Inhibitors Using Docking and 3D-QSAR Approaches
title_short Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B-Raf(V600E)/KDR Inhibitors Using Docking and 3D-QSAR Approaches
title_sort studies on [5,6]-fused bicyclic scaffolds derivatives as potent dual b-raf(v600e)/kdr inhibitors using docking and 3d-qsar approaches
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632759/
https://www.ncbi.nlm.nih.gov/pubmed/26501259
http://dx.doi.org/10.3390/ijms161024451
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