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Structural Bioinformatics and Computational Biochemistry Unit
Dept. of Biochemistry
University of Oxford
South Parks Road
Telephone: 01865 613304
Fax: 01865 613238
Computational Studies of Peptide Transporters to Improve Drug Bioavailability
When a drug is taken orally, it has to pass through the gut lining to enter the blood circulation system before reaching its target. If the drug is hydrophilic it cannot easily diffuse across the hydrophobic membrane, which partly explains why some drugs have very poor bioavailability. Human PepT1, which is a peptide transporter found on the apical epithelial membrane of the small intestine, has been shown to facilitate the absorption of some peptidomimetic drugs e.g. beta-lactam antibiotics. Recent publications of the crystal structure of bacterial peptide transporters (Newstead et al, 2011, Solcan et al, 2012,Lyons et al, 2014) and the large ectodomain (ECD) (Beale et al, 2011) allow us to build the first full length model of human PepT1. My recent work with PepT1 involves:Building homology models for different conformations of PepT1 using different templates for the transmembrane region. MD simulations are performed for each model to illustrate the structural transitions occuring during a transport cycle. Molecular docking of drug molecules on PepT1 binding site to investigate common protein-drug interactions that are essential for binding and transport. Estimation of peptide and drug binding energy using scoring functions and fast end-point free energy calculation methods i.e. LIE and MM/PBSA and comparing our predictions to experimental data from transport assay. The results are further refined by measuring relative free energy of binding using alchemical transformations and thermodynamic integration. Understanding the function of ECD by virtue of bioinformatics studies using multiple sequence and structural alignments. This pursuit will allow us to understand key components of drug translocation via human PepT1 and ultimately inform rational drug design for better bioavailability.
I completed my BSc in Biotechnology in July 2011 at Imperial College London. My final year project was on "Biophysical Aspects in Gene Regulation: Bistability and Hysteresis". This was a systems biology approach to study multistability in gene expression systems of Lac operon and GAL regulon.
Beale JH*, Parker JL*, Samsudin MF*, Barret AL, Senan A, Bird LE, Scott D, Owens RJ, Sansom MSP, Tucker SJ, Meredith D, Fowler PW, Newstead S (2015) Crystal structures of the extracellular domain from PepT1 and PepT2 provide novel insights into mammalian peptide transport. Structure 23, 1889-1899. (doi:10.1016/j.str.2015.07.016)
Samsudin MF, Parker JL, Sansom MSP, Newstead S and Fowler PW. (2015). Accurate prediction of ligand affinities for a peptide transporter. Cell Chem. Biol., In press. (doi:10.1016/j.chembiol.2015.11.015)
Samsudin MF, Sansom MSP, Newstead S and Fowler PW. Substrate promiscuity within the proton-dependent oligopeptide transporter family. Biochemistry, In preparation.
*Joint first authors
|Last updated 27/03/13