Bioavailability through PepT1: the role of computer modelling in intelligent drug design

In addition to being responsible for the majority of absorption of dietary nitrogen, the mammalian proton-coupled di- and tri-peptide transporter PepT1 is also recognised as a major route of drug delivery for several important classes of compound, including beta-lactam antibiotics and angiotensin-converting enzyme inhibitors. Thus there is considerable interest in the PepT1 protein and especially its substrate binding site. In the absence of a crystal structure, computer modelling has been used to try to understand the relationship between PepT1 3D structure and function. Two basic approaches have been taken: modelling the transporter protein, and modelling the substrate. For the former, computer modelling has evolved from early interpretations of the twelve transmembrane domain structure to more recent homology modelling based on recently crystallised bacterial members of the major facilitator superfamily (MFS). Substrate modelling has involved the proposal of a substrate binding template, to which all substrates must conform and from which the affinity of a substrate can be estimated relatively accurately, and identification of points of potential interaction of the substrate with the protein by developing a pharmacophore model of the substrates. Most recently, these two approaches have moved closer together, with the attempted docking of a substrate library onto a homology model of the human PepT1 protein. This article will review these two approaches in which computers have been applied to peptide transport and suggest how such computer modelling could affect drug design and delivery through PepT1.