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Comparing pharmacophore models derived from crystal structures and from molecular dynamics simulations

ABSTRACT: Pharmacophore modeling is a widely used technique in computer-aided drug discovery. Structure-based pharmacophore models of a ligand in complex with a protein have proven to be useful for supporting in silico hit discovery, hit to lead expansion, and lead optimization. As a structure-based...

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Autores principales: Wieder, Marcus, Perricone, Ugo, Seidel, Thomas, Boresch, Stefan, Langer, Thierry
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Vienna 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785218/
https://www.ncbi.nlm.nih.gov/pubmed/27069282
http://dx.doi.org/10.1007/s00706-016-1674-1
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author Wieder, Marcus
Perricone, Ugo
Seidel, Thomas
Boresch, Stefan
Langer, Thierry
author_facet Wieder, Marcus
Perricone, Ugo
Seidel, Thomas
Boresch, Stefan
Langer, Thierry
author_sort Wieder, Marcus
collection PubMed
description ABSTRACT: Pharmacophore modeling is a widely used technique in computer-aided drug discovery. Structure-based pharmacophore models of a ligand in complex with a protein have proven to be useful for supporting in silico hit discovery, hit to lead expansion, and lead optimization. As a structure-based approach it depends on the correct interpretation of ligand–protein interactions. There are legitimate concerns about the fidelity of the bound ligand and about non-physiological contacts with parts of the crystal and the solvent effects that influence the protein structure. A possible way to refine the structure of a protein–ligand system is to use the final structure of a given MD simulation. In this study we compare pharmacophore models built using the initial protein–ligand structure obtained from the protein data bank (PDB) with pharmacophore models built with the final structure of a molecular dynamics simulation. We show that the pharmacophore models differ in feature number and feature type and that the pharmacophore models built from the last structure of a MD simulation shows in some cases better ability to distinguish between active and decoy ligand structures. GRAPHICAL ABSTRACT: [Image: see text]
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spelling pubmed-47852182016-04-09 Comparing pharmacophore models derived from crystal structures and from molecular dynamics simulations Wieder, Marcus Perricone, Ugo Seidel, Thomas Boresch, Stefan Langer, Thierry Monatsh Chem Original Paper ABSTRACT: Pharmacophore modeling is a widely used technique in computer-aided drug discovery. Structure-based pharmacophore models of a ligand in complex with a protein have proven to be useful for supporting in silico hit discovery, hit to lead expansion, and lead optimization. As a structure-based approach it depends on the correct interpretation of ligand–protein interactions. There are legitimate concerns about the fidelity of the bound ligand and about non-physiological contacts with parts of the crystal and the solvent effects that influence the protein structure. A possible way to refine the structure of a protein–ligand system is to use the final structure of a given MD simulation. In this study we compare pharmacophore models built using the initial protein–ligand structure obtained from the protein data bank (PDB) with pharmacophore models built with the final structure of a molecular dynamics simulation. We show that the pharmacophore models differ in feature number and feature type and that the pharmacophore models built from the last structure of a MD simulation shows in some cases better ability to distinguish between active and decoy ligand structures. GRAPHICAL ABSTRACT: [Image: see text] Springer Vienna 2016-02-22 2016 /pmc/articles/PMC4785218/ /pubmed/27069282 http://dx.doi.org/10.1007/s00706-016-1674-1 Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Paper
Wieder, Marcus
Perricone, Ugo
Seidel, Thomas
Boresch, Stefan
Langer, Thierry
Comparing pharmacophore models derived from crystal structures and from molecular dynamics simulations
title Comparing pharmacophore models derived from crystal structures and from molecular dynamics simulations
title_full Comparing pharmacophore models derived from crystal structures and from molecular dynamics simulations
title_fullStr Comparing pharmacophore models derived from crystal structures and from molecular dynamics simulations
title_full_unstemmed Comparing pharmacophore models derived from crystal structures and from molecular dynamics simulations
title_short Comparing pharmacophore models derived from crystal structures and from molecular dynamics simulations
title_sort comparing pharmacophore models derived from crystal structures and from molecular dynamics simulations
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785218/
https://www.ncbi.nlm.nih.gov/pubmed/27069282
http://dx.doi.org/10.1007/s00706-016-1674-1
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