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

作者：Samsudin Firdaus; Parker Joanne L; Sansom Mark S P; Newstead Simon^*; Fowler Philip W^*

来源：Cell Chemical Biology, 2016, 23(2): 299-309.

DOI：10.1016/j.chembiol.2015.11.015

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 beta-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.

• 出版日期2016-2-18