Predicting inactive conformations of protein kinases using active structures: conformational selection of type-II inhibitors.

Protein kinases have been found to possess two characteristic conformations in their activation-loops: the active DFG-in conformation and the inactive DFG-out conformation. Recently, it has been very interesting to develop type-II inhibitors which target the DFG-out conformation and are more specifi...

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Autores principales:	Min Xu, Lu Yu, Bo Wan, Long Yu, Qiang Huang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4da3eac233794f118169058ba5921358
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spelling	oai:doaj.org-article:4da3eac233794f118169058ba59213582021-11-18T06:49:16ZPredicting inactive conformations of protein kinases using active structures: conformational selection of type-II inhibitors.1932-620310.1371/journal.pone.0022644https://doaj.org/article/4da3eac233794f118169058ba59213582011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21818358/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Protein kinases have been found to possess two characteristic conformations in their activation-loops: the active DFG-in conformation and the inactive DFG-out conformation. Recently, it has been very interesting to develop type-II inhibitors which target the DFG-out conformation and are more specific than the type-I inhibitors binding to the active DFG-in conformation. However, solving crystal structures of kinases with the DFG-out conformation remains a challenge, and this seriously hampers the application of the structure-based approaches in development of novel type-II inhibitors. To overcome this limitation, here we present a computational approach for predicting the DFG-out inactive conformation using the DFG-in active structures, and develop related conformational selection protocols for the uses of the predicted DFG-out models in the binding pose prediction and virtual screening of type-II ligands. With the DFG-out models, we predicted the binding poses for known type-II inhibitors, and the results were found in good agreement with the X-ray crystal structures. We also tested the abilities of the DFG-out models to recognize their specific type-II inhibitors by screening a database of small molecules. The AUC (area under curve) results indicated that the predicted DFG-out models were selective toward their specific type-II inhibitors. Therefore, the computational approach and protocols presented in this study are very promising for the structure-based design and screening of novel type-II kinase inhibitors.Min XuLu YuBo WanLong YuQiang HuangPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 7, p e22644 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Min Xu Lu Yu Bo Wan Long Yu Qiang Huang Predicting inactive conformations of protein kinases using active structures: conformational selection of type-II inhibitors.
description	Protein kinases have been found to possess two characteristic conformations in their activation-loops: the active DFG-in conformation and the inactive DFG-out conformation. Recently, it has been very interesting to develop type-II inhibitors which target the DFG-out conformation and are more specific than the type-I inhibitors binding to the active DFG-in conformation. However, solving crystal structures of kinases with the DFG-out conformation remains a challenge, and this seriously hampers the application of the structure-based approaches in development of novel type-II inhibitors. To overcome this limitation, here we present a computational approach for predicting the DFG-out inactive conformation using the DFG-in active structures, and develop related conformational selection protocols for the uses of the predicted DFG-out models in the binding pose prediction and virtual screening of type-II ligands. With the DFG-out models, we predicted the binding poses for known type-II inhibitors, and the results were found in good agreement with the X-ray crystal structures. We also tested the abilities of the DFG-out models to recognize their specific type-II inhibitors by screening a database of small molecules. The AUC (area under curve) results indicated that the predicted DFG-out models were selective toward their specific type-II inhibitors. Therefore, the computational approach and protocols presented in this study are very promising for the structure-based design and screening of novel type-II kinase inhibitors.
format	article
author	Min Xu Lu Yu Bo Wan Long Yu Qiang Huang
author_facet	Min Xu Lu Yu Bo Wan Long Yu Qiang Huang
author_sort	Min Xu
title	Predicting inactive conformations of protein kinases using active structures: conformational selection of type-II inhibitors.
title_short	Predicting inactive conformations of protein kinases using active structures: conformational selection of type-II inhibitors.
title_full	Predicting inactive conformations of protein kinases using active structures: conformational selection of type-II inhibitors.
title_fullStr	Predicting inactive conformations of protein kinases using active structures: conformational selection of type-II inhibitors.
title_full_unstemmed	Predicting inactive conformations of protein kinases using active structures: conformational selection of type-II inhibitors.
title_sort	predicting inactive conformations of protein kinases using active structures: conformational selection of type-ii inhibitors.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/4da3eac233794f118169058ba5921358
work_keys_str_mv	AT minxu predictinginactiveconformationsofproteinkinasesusingactivestructuresconformationalselectionoftypeiiinhibitors AT luyu predictinginactiveconformationsofproteinkinasesusingactivestructuresconformationalselectionoftypeiiinhibitors AT bowan predictinginactiveconformationsofproteinkinasesusingactivestructuresconformationalselectionoftypeiiinhibitors AT longyu predictinginactiveconformationsofproteinkinasesusingactivestructuresconformationalselectionoftypeiiinhibitors AT qianghuang predictinginactiveconformationsofproteinkinasesusingactivestructuresconformationalselectionoftypeiiinhibitors
_version_	1718424349673783296

Predicting inactive conformations of protein kinases using active structures: conformational selection of type-II inhibitors.

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