David Foley - Bioavailability Through PepT1: The Role of Computer Modelling in Intelligent Drug Design

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  Publication Details (including relevant citation   information):

  Foley, David W.; Rajamanickam, Jeyaganesh; Bailey, Patrick D.;   Meredith, David

  Current Computer - Aided Drug Design, 2010,   6, 68-78

  DOI: 10.2174/157340910790980133

  Review

  Abstract:

  In addition to being responsible for the majority of absorption   of dietary nitrogen, the mammalian proton-coupled di- and   tripeptide transporter PepT1 is also recognised as a major route   of drug delivery for several important classes of compound,   including β- 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.

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