title: Accurate Prediction of Ligand Affinities for a Proton-Dependent Oligopeptide Transporter.
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.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Firdaus
authors.initials: F
authors.lastname: Samsudin
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Parker
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Mark S P
authors.initials: MSP
authors.lastname: Sansom
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address: simon.newstead@bioch.ox.ac.uk.
authors.forename: Simon
authors.initials: S
authors.lastname: Newstead
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address: philip.fowler@bioch.ox.ac.uk.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Fowler
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism*; D000074011:Peptide Transporter 1; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism*; D027981:Symporters / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D000900:Anti-Bacterial Agents; D008024:Ligands; D009842:Oligopeptides; D000074011:Peptide Transporter 1; D011355:Prodrugs; C082186:SLC15A1 protein, human; D027981:Symporters