Identification of ligand binding sites in intrinsically disordered proteins with a differential binding score

Abstract Screening ligands directly binding to an ensemble of intrinsically disordered proteins (IDP) to discover potential hits or leads for new drugs is an emerging but challenging area as IDPs lack well-defined and ordered 3D-protein structures. To explore a new IDP-based rational drug discovery...

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Autores principales:	Qiao-Hong Chen, V. V. Krishnan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/22f7debeb371435989690ab7df242c36
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spelling	oai:doaj.org-article:22f7debeb371435989690ab7df242c362021-11-21T12:16:43ZIdentification of ligand binding sites in intrinsically disordered proteins with a differential binding score10.1038/s41598-021-00869-42045-2322https://doaj.org/article/22f7debeb371435989690ab7df242c362021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-00869-4https://doaj.org/toc/2045-2322Abstract Screening ligands directly binding to an ensemble of intrinsically disordered proteins (IDP) to discover potential hits or leads for new drugs is an emerging but challenging area as IDPs lack well-defined and ordered 3D-protein structures. To explore a new IDP-based rational drug discovery strategy, a differential binding score (DIBS) is defined. The basis of DIBS is to quantitatively determine the binding preference of a ligand to an ensemble of conformations specified by IDP versus such preferences to an ensemble of random coil conformations of the same protein. Ensemble docking procedures performed on repeated sampling of conformations, and the results tested for statistical significance determine the preferential ligand binding sites of the IDP. The results of this approach closely reproduce the experimental data from recent literature on the binding of the ligand epigallocatechin gallate (EGCG) to the intrinsically disordered N-terminal domain of the tumor suppressor p53. Combining established approaches in developing a new method to screen ligands against IDPs could be valuable as a screening tool for IDP-based drug discovery.Qiao-Hong ChenV. V. KrishnanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Qiao-Hong Chen V. V. Krishnan Identification of ligand binding sites in intrinsically disordered proteins with a differential binding score
description	Abstract Screening ligands directly binding to an ensemble of intrinsically disordered proteins (IDP) to discover potential hits or leads for new drugs is an emerging but challenging area as IDPs lack well-defined and ordered 3D-protein structures. To explore a new IDP-based rational drug discovery strategy, a differential binding score (DIBS) is defined. The basis of DIBS is to quantitatively determine the binding preference of a ligand to an ensemble of conformations specified by IDP versus such preferences to an ensemble of random coil conformations of the same protein. Ensemble docking procedures performed on repeated sampling of conformations, and the results tested for statistical significance determine the preferential ligand binding sites of the IDP. The results of this approach closely reproduce the experimental data from recent literature on the binding of the ligand epigallocatechin gallate (EGCG) to the intrinsically disordered N-terminal domain of the tumor suppressor p53. Combining established approaches in developing a new method to screen ligands against IDPs could be valuable as a screening tool for IDP-based drug discovery.
format	article
author	Qiao-Hong Chen V. V. Krishnan
author_facet	Qiao-Hong Chen V. V. Krishnan
author_sort	Qiao-Hong Chen
title	Identification of ligand binding sites in intrinsically disordered proteins with a differential binding score
title_short	Identification of ligand binding sites in intrinsically disordered proteins with a differential binding score
title_full	Identification of ligand binding sites in intrinsically disordered proteins with a differential binding score
title_fullStr	Identification of ligand binding sites in intrinsically disordered proteins with a differential binding score
title_full_unstemmed	Identification of ligand binding sites in intrinsically disordered proteins with a differential binding score
title_sort	identification of ligand binding sites in intrinsically disordered proteins with a differential binding score
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/22f7debeb371435989690ab7df242c36
work_keys_str_mv	AT qiaohongchen identificationofligandbindingsitesinintrinsicallydisorderedproteinswithadifferentialbindingscore AT vvkrishnan identificationofligandbindingsitesinintrinsicallydisorderedproteinswithadifferentialbindingscore
_version_	1718419113045393408

Identification of ligand binding sites in intrinsically disordered proteins with a differential binding score

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