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Cell Chem Biol. 2016 Feb 18;23(2):299-309. doi: 10.1016/j.chembiol.2015.11.015. Epub 2016 Jan 28.

Accurate Prediction of Ligand Affinities for a Proton-Dependent Oligopeptide Transporter.

Author information

1
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
2
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address: simon.newstead@bioch.ox.ac.uk.
3
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address: philip.fowler@bioch.ox.ac.uk.

Abstract

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 ?-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.

PMID:
27028887
PMCID:
PMC4760754
DOI:
10.1016/j.chembiol.2015.11.015
[Indexed for MEDLINE]
Free PMC Article

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