Comparing binding modes of analogous fragments using NMR in fragment-based drug design: application to PRDX5.

Fragment-based drug design is one of the most promising approaches for discovering novel and potent inhibitors against therapeutic targets. The first step of the process consists of identifying fragments that bind the protein target. The determination of the fragment binding mode plays a major role...

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Autores principales:	Clémentine Aguirre, Tim ten Brink, Jean-François Guichou, Olivier Cala, Isabelle Krimm
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ac6e427c7187469a8cf78c8d421844f7
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id	oai:doaj.org-article:ac6e427c7187469a8cf78c8d421844f7
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spelling	oai:doaj.org-article:ac6e427c7187469a8cf78c8d421844f72021-11-25T06:08:28ZComparing binding modes of analogous fragments using NMR in fragment-based drug design: application to PRDX5.1932-620310.1371/journal.pone.0102300https://doaj.org/article/ac6e427c7187469a8cf78c8d421844f72014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25025339/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Fragment-based drug design is one of the most promising approaches for discovering novel and potent inhibitors against therapeutic targets. The first step of the process consists of identifying fragments that bind the protein target. The determination of the fragment binding mode plays a major role in the selection of the fragment hits that will be processed into drug-like compounds. Comparing the binding modes of analogous fragments is a critical task, not only to identify specific interactions between the protein target and the fragment, but also to verify whether the binding mode is conserved or differs according to the fragment modification. While X-ray crystallography is the technique of choice, NMR methods are helpful when this fails. We show here how the ligand-observed saturation transfer difference (STD) experiment and the protein-observed 15N-HSQC experiment, two popular NMR screening experiments, can be used to compare the binding modes of analogous fragments. We discuss the application and limitations of these approaches based on STD-epitope mapping, chemical shift perturbation (CSP) calculation and comparative CSP sign analysis, using the human peroxiredoxin 5 as a protein model.Clémentine AguirreTim ten BrinkJean-François GuichouOlivier CalaIsabelle KrimmPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 7, p e102300 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Clémentine Aguirre Tim ten Brink Jean-François Guichou Olivier Cala Isabelle Krimm Comparing binding modes of analogous fragments using NMR in fragment-based drug design: application to PRDX5.
description	Fragment-based drug design is one of the most promising approaches for discovering novel and potent inhibitors against therapeutic targets. The first step of the process consists of identifying fragments that bind the protein target. The determination of the fragment binding mode plays a major role in the selection of the fragment hits that will be processed into drug-like compounds. Comparing the binding modes of analogous fragments is a critical task, not only to identify specific interactions between the protein target and the fragment, but also to verify whether the binding mode is conserved or differs according to the fragment modification. While X-ray crystallography is the technique of choice, NMR methods are helpful when this fails. We show here how the ligand-observed saturation transfer difference (STD) experiment and the protein-observed 15N-HSQC experiment, two popular NMR screening experiments, can be used to compare the binding modes of analogous fragments. We discuss the application and limitations of these approaches based on STD-epitope mapping, chemical shift perturbation (CSP) calculation and comparative CSP sign analysis, using the human peroxiredoxin 5 as a protein model.
format	article
author	Clémentine Aguirre Tim ten Brink Jean-François Guichou Olivier Cala Isabelle Krimm
author_facet	Clémentine Aguirre Tim ten Brink Jean-François Guichou Olivier Cala Isabelle Krimm
author_sort	Clémentine Aguirre
title	Comparing binding modes of analogous fragments using NMR in fragment-based drug design: application to PRDX5.
title_short	Comparing binding modes of analogous fragments using NMR in fragment-based drug design: application to PRDX5.
title_full	Comparing binding modes of analogous fragments using NMR in fragment-based drug design: application to PRDX5.
title_fullStr	Comparing binding modes of analogous fragments using NMR in fragment-based drug design: application to PRDX5.
title_full_unstemmed	Comparing binding modes of analogous fragments using NMR in fragment-based drug design: application to PRDX5.
title_sort	comparing binding modes of analogous fragments using nmr in fragment-based drug design: application to prdx5.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/ac6e427c7187469a8cf78c8d421844f7
work_keys_str_mv	AT clementineaguirre comparingbindingmodesofanalogousfragmentsusingnmrinfragmentbaseddrugdesignapplicationtoprdx5 AT timtenbrink comparingbindingmodesofanalogousfragmentsusingnmrinfragmentbaseddrugdesignapplicationtoprdx5 AT jeanfrancoisguichou comparingbindingmodesofanalogousfragmentsusingnmrinfragmentbaseddrugdesignapplicationtoprdx5 AT oliviercala comparingbindingmodesofanalogousfragmentsusingnmrinfragmentbaseddrugdesignapplicationtoprdx5 AT isabellekrimm comparingbindingmodesofanalogousfragmentsusingnmrinfragmentbaseddrugdesignapplicationtoprdx5
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Comparing binding modes of analogous fragments using NMR in fragment-based drug design: application to PRDX5.

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