Accurate Prediction of Ligand Affinities for a Proton-Dependent Oligopeptide Transporter. Issue 2 (18th February 2016)

• Record Type: Journal Article
• Authors: Samsudin, Firdaus; Parker, Joanne L.; Sansom, Mark S.P.; Newstead, Simon; Fowler, Philip W.
• Is Part Of: Cell chemical biology. Volume 23:Issue 2(2016)
• Page Start: 299
• Page End: 309
• Publication Date: 2016-02-18
• Subjects: Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2015.11.015
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: A hierarchical computational approach determines ligand affinities to transporters Lysine-containing dipeptides proposed to bind vertically like a tripeptide Experimental structures are vital for the accurate prediction of affinities A model of prodrug interactions to human PepT1 is suggested Abstract : Samsudin et al. demonstrate how a hierarchical free energy method can predict the affinities of ligands for a peptide transporter protein. This approach may be used to optimize drug-transporter interactions.