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Truly Target-Focused Pharmacophore Modeling: A Novel Tool for Mapping Intermolecular Surfaces
Pharmacophore models are an accurate and minimal tridimensional abstraction of intermolecular interactions between chemical structures, usually derived from a group of molecules or from a ligand-target complex. Only a limited amount of solutions exists to model comprehensive pharmacophores using the...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222449/ https://www.ncbi.nlm.nih.gov/pubmed/30082611 http://dx.doi.org/10.3390/molecules23081959 |
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author | Mortier, Jérémie Dhakal, Pratik Volkamer, Andrea |
author_facet | Mortier, Jérémie Dhakal, Pratik Volkamer, Andrea |
author_sort | Mortier, Jérémie |
collection | PubMed |
description | Pharmacophore models are an accurate and minimal tridimensional abstraction of intermolecular interactions between chemical structures, usually derived from a group of molecules or from a ligand-target complex. Only a limited amount of solutions exists to model comprehensive pharmacophores using the information of a particular target structure without knowledge of any binding ligand. In this work, an automated and customable tool for truly target-focused (T²F) pharmacophore modeling is introduced. Key molecular interaction fields of a macromolecular structure are calculated using the AutoGRID energy functions. The most relevant points are selected by a newly developed filtering cascade and clustered to pharmacophore features with a density-based algorithm. Using five different protein classes, the ability of this method to identify essential pharmacophore features was compared to structure-based pharmacophores derived from ligand-target interactions. This method represents an extremely valuable instrument for drug design in a situation of scarce ligand information available, but also in the case of underexplored therapeutic targets, as well as to investigate protein allosteric pockets and protein-protein interactions. |
format | Online Article Text |
id | pubmed-6222449 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-62224492018-11-13 Truly Target-Focused Pharmacophore Modeling: A Novel Tool for Mapping Intermolecular Surfaces Mortier, Jérémie Dhakal, Pratik Volkamer, Andrea Molecules Article Pharmacophore models are an accurate and minimal tridimensional abstraction of intermolecular interactions between chemical structures, usually derived from a group of molecules or from a ligand-target complex. Only a limited amount of solutions exists to model comprehensive pharmacophores using the information of a particular target structure without knowledge of any binding ligand. In this work, an automated and customable tool for truly target-focused (T²F) pharmacophore modeling is introduced. Key molecular interaction fields of a macromolecular structure are calculated using the AutoGRID energy functions. The most relevant points are selected by a newly developed filtering cascade and clustered to pharmacophore features with a density-based algorithm. Using five different protein classes, the ability of this method to identify essential pharmacophore features was compared to structure-based pharmacophores derived from ligand-target interactions. This method represents an extremely valuable instrument for drug design in a situation of scarce ligand information available, but also in the case of underexplored therapeutic targets, as well as to investigate protein allosteric pockets and protein-protein interactions. MDPI 2018-08-06 /pmc/articles/PMC6222449/ /pubmed/30082611 http://dx.doi.org/10.3390/molecules23081959 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Mortier, Jérémie Dhakal, Pratik Volkamer, Andrea Truly Target-Focused Pharmacophore Modeling: A Novel Tool for Mapping Intermolecular Surfaces |
title | Truly Target-Focused Pharmacophore Modeling: A Novel Tool for Mapping Intermolecular Surfaces |
title_full | Truly Target-Focused Pharmacophore Modeling: A Novel Tool for Mapping Intermolecular Surfaces |
title_fullStr | Truly Target-Focused Pharmacophore Modeling: A Novel Tool for Mapping Intermolecular Surfaces |
title_full_unstemmed | Truly Target-Focused Pharmacophore Modeling: A Novel Tool for Mapping Intermolecular Surfaces |
title_short | Truly Target-Focused Pharmacophore Modeling: A Novel Tool for Mapping Intermolecular Surfaces |
title_sort | truly target-focused pharmacophore modeling: a novel tool for mapping intermolecular surfaces |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222449/ https://www.ncbi.nlm.nih.gov/pubmed/30082611 http://dx.doi.org/10.3390/molecules23081959 |
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