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Discovery of novel inhibitors disrupting HIF-1α/von Hippel–Lindau interaction through shape-based screening and cascade docking

Major research efforts have been devoted to the discovery and development of new chemical entities that could inhibit the protein–protein interaction between HIF-1α and the von Hippel–Lindau protein (pVHL), which serves as the substrate recognition subunit of an E3 ligase and is regarded as a crucia...

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Autores principales: Xue, Xin, Zhao, Ning-Yi, Yu, Hai-Tao, Sun, Yuan, Kang, Chen, Huang, Qiong-Bin, Sun, Hao-Peng, Wang, Xiao-Long, Li, Nian-Guang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: PeerJ Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5162400/
https://www.ncbi.nlm.nih.gov/pubmed/27994971
http://dx.doi.org/10.7717/peerj.2757
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author Xue, Xin
Zhao, Ning-Yi
Yu, Hai-Tao
Sun, Yuan
Kang, Chen
Huang, Qiong-Bin
Sun, Hao-Peng
Wang, Xiao-Long
Li, Nian-Guang
author_facet Xue, Xin
Zhao, Ning-Yi
Yu, Hai-Tao
Sun, Yuan
Kang, Chen
Huang, Qiong-Bin
Sun, Hao-Peng
Wang, Xiao-Long
Li, Nian-Guang
author_sort Xue, Xin
collection PubMed
description Major research efforts have been devoted to the discovery and development of new chemical entities that could inhibit the protein–protein interaction between HIF-1α and the von Hippel–Lindau protein (pVHL), which serves as the substrate recognition subunit of an E3 ligase and is regarded as a crucial drug target in cancer, chronic anemia, and ischemia. Currently there is only one class of compounds available to interdict the HIF-1α/pVHL interaction, urging the need to discover chemical inhibitors with more diversified structures. We report here a strategy combining shape-based virtual screening and cascade docking to identify new chemical scaffolds for the designing of novel inhibitors. Based on this strategy, nine active hits have been identified and the most active hit, 9 (ZINC13466751), showed comparable activity to pVHL with an IC50 of 2.0 ± 0.14 µM, showing the great potential of utilizing these compounds for further optimization and serving as drug candidates for the inhibition of HIF-1α/von Hippel–Lindau interaction.
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spelling pubmed-51624002016-12-19 Discovery of novel inhibitors disrupting HIF-1α/von Hippel–Lindau interaction through shape-based screening and cascade docking Xue, Xin Zhao, Ning-Yi Yu, Hai-Tao Sun, Yuan Kang, Chen Huang, Qiong-Bin Sun, Hao-Peng Wang, Xiao-Long Li, Nian-Guang PeerJ Biochemistry Major research efforts have been devoted to the discovery and development of new chemical entities that could inhibit the protein–protein interaction between HIF-1α and the von Hippel–Lindau protein (pVHL), which serves as the substrate recognition subunit of an E3 ligase and is regarded as a crucial drug target in cancer, chronic anemia, and ischemia. Currently there is only one class of compounds available to interdict the HIF-1α/pVHL interaction, urging the need to discover chemical inhibitors with more diversified structures. We report here a strategy combining shape-based virtual screening and cascade docking to identify new chemical scaffolds for the designing of novel inhibitors. Based on this strategy, nine active hits have been identified and the most active hit, 9 (ZINC13466751), showed comparable activity to pVHL with an IC50 of 2.0 ± 0.14 µM, showing the great potential of utilizing these compounds for further optimization and serving as drug candidates for the inhibition of HIF-1α/von Hippel–Lindau interaction. PeerJ Inc. 2016-12-15 /pmc/articles/PMC5162400/ /pubmed/27994971 http://dx.doi.org/10.7717/peerj.2757 Text en ©2016 Xue et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.
spellingShingle Biochemistry
Xue, Xin
Zhao, Ning-Yi
Yu, Hai-Tao
Sun, Yuan
Kang, Chen
Huang, Qiong-Bin
Sun, Hao-Peng
Wang, Xiao-Long
Li, Nian-Guang
Discovery of novel inhibitors disrupting HIF-1α/von Hippel–Lindau interaction through shape-based screening and cascade docking
title Discovery of novel inhibitors disrupting HIF-1α/von Hippel–Lindau interaction through shape-based screening and cascade docking
title_full Discovery of novel inhibitors disrupting HIF-1α/von Hippel–Lindau interaction through shape-based screening and cascade docking
title_fullStr Discovery of novel inhibitors disrupting HIF-1α/von Hippel–Lindau interaction through shape-based screening and cascade docking
title_full_unstemmed Discovery of novel inhibitors disrupting HIF-1α/von Hippel–Lindau interaction through shape-based screening and cascade docking
title_short Discovery of novel inhibitors disrupting HIF-1α/von Hippel–Lindau interaction through shape-based screening and cascade docking
title_sort discovery of novel inhibitors disrupting hif-1α/von hippel–lindau interaction through shape-based screening and cascade docking
topic Biochemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5162400/
https://www.ncbi.nlm.nih.gov/pubmed/27994971
http://dx.doi.org/10.7717/peerj.2757
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