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,...
| Main Authors: | , , , , |
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| Format: | Journal article |
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Cell Press
2016
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| _version_ | 1797095921266196480 |
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| author | Newstead, S Samsudin, F Parker, J Sansom, M Fowler, P |
| author_facet | Newstead, S Samsudin, F Parker, J Sansom, M Fowler, P |
| author_sort | Newstead, S |
| collection | OXFORD |
| 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, PepTSt, 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. |
| first_indexed | 2024-03-07T04:34:52Z |
| format | Journal article |
| id | oxford-uuid:cf9297be-e847-4ef8-b12d-04c748c5d5dc |
| institution | University of Oxford |
| last_indexed | 2024-03-07T04:34:52Z |
| publishDate | 2016 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:cf9297be-e847-4ef8-b12d-04c748c5d5dc2022-03-27T07:43:37ZAccurate Prediction of Ligand Affinities for a Proton-Dependent Oligopeptide TransporterJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:cf9297be-e847-4ef8-b12d-04c748c5d5dcSymplectic Elements at OxfordCell Press2016Newstead, SSamsudin, FParker, JSansom, MFowler, PMembrane 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, PepTSt, 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. |
| spellingShingle | Newstead, S Samsudin, F Parker, J Sansom, M Fowler, P 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 |
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