Drug discovery using chemical systems biology: identification of the protein-ligand binding network to explain the side effects of CETP inhibitors.

Systematic identification of protein-drug interaction networks is crucial to correlate complex modes of drug action to clinical indications. We introduce a novel computational strategy to identify protein-ligand binding profiles on a genome-wide scale and apply it to elucidating the molecular mechan...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Li Xie, Jerry Li, Lei Xie, Philip E Bourne
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/91767499f71d4169b7fa9ec4fd7401f7
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:91767499f71d4169b7fa9ec4fd7401f7
record_format	dspace
spelling	oai:doaj.org-article:91767499f71d4169b7fa9ec4fd7401f72021-11-25T05:42:24ZDrug discovery using chemical systems biology: identification of the protein-ligand binding network to explain the side effects of CETP inhibitors.1553-734X1553-735810.1371/journal.pcbi.1000387https://doaj.org/article/91767499f71d4169b7fa9ec4fd7401f72009-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19436720/pdf/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Systematic identification of protein-drug interaction networks is crucial to correlate complex modes of drug action to clinical indications. We introduce a novel computational strategy to identify protein-ligand binding profiles on a genome-wide scale and apply it to elucidating the molecular mechanisms associated with the adverse drug effects of Cholesteryl Ester Transfer Protein (CETP) inhibitors. CETP inhibitors are a new class of preventive therapies for the treatment of cardiovascular disease. However, clinical studies indicated that one CETP inhibitor, Torcetrapib, has deadly off-target effects as a result of hypertension, and hence it has been withdrawn from phase III clinical trials. We have identified a panel of off-targets for Torcetrapib and other CETP inhibitors from the human structural genome and map those targets to biological pathways via the literature. The predicted protein-ligand network is consistent with experimental results from multiple sources and reveals that the side-effect of CETP inhibitors is modulated through the combinatorial control of multiple interconnected pathways. Given that combinatorial control is a common phenomenon observed in many biological processes, our findings suggest that adverse drug effects might be minimized by fine-tuning multiple off-target interactions using single or multiple therapies. This work extends the scope of chemogenomics approaches and exemplifies the role that systems biology has in the future of drug discovery.Li XieJerry LiLei XiePhilip E BournePublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 5, Iss 5, p e1000387 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Li Xie Jerry Li Lei Xie Philip E Bourne Drug discovery using chemical systems biology: identification of the protein-ligand binding network to explain the side effects of CETP inhibitors.
description	Systematic identification of protein-drug interaction networks is crucial to correlate complex modes of drug action to clinical indications. We introduce a novel computational strategy to identify protein-ligand binding profiles on a genome-wide scale and apply it to elucidating the molecular mechanisms associated with the adverse drug effects of Cholesteryl Ester Transfer Protein (CETP) inhibitors. CETP inhibitors are a new class of preventive therapies for the treatment of cardiovascular disease. However, clinical studies indicated that one CETP inhibitor, Torcetrapib, has deadly off-target effects as a result of hypertension, and hence it has been withdrawn from phase III clinical trials. We have identified a panel of off-targets for Torcetrapib and other CETP inhibitors from the human structural genome and map those targets to biological pathways via the literature. The predicted protein-ligand network is consistent with experimental results from multiple sources and reveals that the side-effect of CETP inhibitors is modulated through the combinatorial control of multiple interconnected pathways. Given that combinatorial control is a common phenomenon observed in many biological processes, our findings suggest that adverse drug effects might be minimized by fine-tuning multiple off-target interactions using single or multiple therapies. This work extends the scope of chemogenomics approaches and exemplifies the role that systems biology has in the future of drug discovery.
format	article
author	Li Xie Jerry Li Lei Xie Philip E Bourne
author_facet	Li Xie Jerry Li Lei Xie Philip E Bourne
author_sort	Li Xie
title	Drug discovery using chemical systems biology: identification of the protein-ligand binding network to explain the side effects of CETP inhibitors.
title_short	Drug discovery using chemical systems biology: identification of the protein-ligand binding network to explain the side effects of CETP inhibitors.
title_full	Drug discovery using chemical systems biology: identification of the protein-ligand binding network to explain the side effects of CETP inhibitors.
title_fullStr	Drug discovery using chemical systems biology: identification of the protein-ligand binding network to explain the side effects of CETP inhibitors.
title_full_unstemmed	Drug discovery using chemical systems biology: identification of the protein-ligand binding network to explain the side effects of CETP inhibitors.
title_sort	drug discovery using chemical systems biology: identification of the protein-ligand binding network to explain the side effects of cetp inhibitors.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/91767499f71d4169b7fa9ec4fd7401f7
work_keys_str_mv	AT lixie drugdiscoveryusingchemicalsystemsbiologyidentificationoftheproteinligandbindingnetworktoexplainthesideeffectsofcetpinhibitors AT jerryli drugdiscoveryusingchemicalsystemsbiologyidentificationoftheproteinligandbindingnetworktoexplainthesideeffectsofcetpinhibitors AT leixie drugdiscoveryusingchemicalsystemsbiologyidentificationoftheproteinligandbindingnetworktoexplainthesideeffectsofcetpinhibitors AT philipebourne drugdiscoveryusingchemicalsystemsbiologyidentificationoftheproteinligandbindingnetworktoexplainthesideeffectsofcetpinhibitors
_version_	1718414530553315328

Drug discovery using chemical systems biology: identification of the protein-ligand binding network to explain the side effects of CETP inhibitors.

Ejemplares similares