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Accurate Prediction of Ligand Affinities for a Proton-Dependent Oligopeptide Transporter
Membrane transporters are critical modulators of drug pharmacokinetics, efficacy, and safety. One example is the proton-dependent oligopeptide transporter PepT1, also known as SLC15A1, which is responsible for the uptake of the β-lactam antibiotics and various peptide-based prodrugs. In this study,...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760754/ https://www.ncbi.nlm.nih.gov/pubmed/27028887 http://dx.doi.org/10.1016/j.chembiol.2015.11.015 |
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author | Samsudin, Firdaus Parker, Joanne L. Sansom, Mark S.P. Newstead, Simon Fowler, Philip W. |
author_facet | Samsudin, Firdaus Parker, Joanne L. Sansom, Mark S.P. Newstead, Simon Fowler, Philip W. |
author_sort | Samsudin, Firdaus |
collection | PubMed |
description | Membrane transporters are critical modulators of drug pharmacokinetics, efficacy, and safety. One example is the proton-dependent oligopeptide transporter PepT1, also known as SLC15A1, which is responsible for the uptake of the β-lactam antibiotics and various peptide-based prodrugs. In this study, we modeled the binding of various peptides to a bacterial homolog, PepT(St), and evaluated a range of computational methods for predicting the free energy of binding. Our results show that a hybrid approach (endpoint methods to classify peptides into good and poor binders and a theoretically exact method for refinement) is able to accurately predict affinities, which we validated using proteoliposome transport assays. Applying the method to a homology model of PepT1 suggests that the approach requires a high-quality structure to be accurate. Our study provides a blueprint for extending these computational methodologies to other pharmaceutically important transporter families. |
format | Online Article Text |
id | pubmed-4760754 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-47607542016-03-04 Accurate Prediction of Ligand Affinities for a Proton-Dependent Oligopeptide Transporter Samsudin, Firdaus Parker, Joanne L. Sansom, Mark S.P. Newstead, Simon Fowler, Philip W. Cell Chem Biol Resource Membrane transporters are critical modulators of drug pharmacokinetics, efficacy, and safety. One example is the proton-dependent oligopeptide transporter PepT1, also known as SLC15A1, which is responsible for the uptake of the β-lactam antibiotics and various peptide-based prodrugs. In this study, we modeled the binding of various peptides to a bacterial homolog, PepT(St), and evaluated a range of computational methods for predicting the free energy of binding. Our results show that a hybrid approach (endpoint methods to classify peptides into good and poor binders and a theoretically exact method for refinement) is able to accurately predict affinities, which we validated using proteoliposome transport assays. Applying the method to a homology model of PepT1 suggests that the approach requires a high-quality structure to be accurate. Our study provides a blueprint for extending these computational methodologies to other pharmaceutically important transporter families. Cell Press 2016-02-18 /pmc/articles/PMC4760754/ /pubmed/27028887 http://dx.doi.org/10.1016/j.chembiol.2015.11.015 Text en © 2016 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Resource Samsudin, Firdaus Parker, Joanne L. Sansom, Mark S.P. Newstead, Simon Fowler, Philip W. Accurate Prediction of Ligand Affinities for a Proton-Dependent Oligopeptide Transporter |
title | Accurate Prediction of Ligand Affinities for a Proton-Dependent Oligopeptide Transporter |
title_full | Accurate Prediction of Ligand Affinities for a Proton-Dependent Oligopeptide Transporter |
title_fullStr | Accurate Prediction of Ligand Affinities for a Proton-Dependent Oligopeptide Transporter |
title_full_unstemmed | Accurate Prediction of Ligand Affinities for a Proton-Dependent Oligopeptide Transporter |
title_short | Accurate Prediction of Ligand Affinities for a Proton-Dependent Oligopeptide Transporter |
title_sort | accurate prediction of ligand affinities for a proton-dependent oligopeptide transporter |
topic | Resource |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760754/ https://www.ncbi.nlm.nih.gov/pubmed/27028887 http://dx.doi.org/10.1016/j.chembiol.2015.11.015 |
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