by Elena Dolghih, Clifford Bryant, Adan R. Renslo, Matthew P. Jacobson
P-glycoprotein (P-gp) is an ATP-dependent transport protein that is selectively expressed at entry points of xenobiotics where, acting as an efflux pump, it prevents their entering sensitive organs. The protein also plays a key role in the absorption and blood-brain barrier penetration of many drugs, while its overexpression in cancer cells has been linked to multidrug resistance in tumors. The recent publication of the mouse P-gp crystal structure revealed a large and hydrophobic binding cavity with no clearly defined sub-sites that supports an “induced-fit” ligand binding model. We employed flexible receptor docking to develop a new prediction algorithm for P-gp binding specificity. We tested the ability of this method to differentiate between binders and nonbinders of P-gp using consistently measured experimental data from P-gp efflux and calcein-inhibition assays. We also subjected the model to a blind test on a series of peptidic cysteine protease inhibitors, confirming the ability to predict compounds more likely to be P-gp substrates. Finally, we used the method to predict cellular metabolites that may be P-gp substrates. Overall, our results suggest that many P-gp substrates bind deeper in the cavity than the cyclic peptide in the crystal structure and that specificity in P-gp is better understood in terms of physicochemical properties of the ligands (and the binding site), rather than being defined by specific sub-sites.
June 23, 2011
PLOS – Computational Biology
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by Combs DJ, Lokey RS
Peptoids (N-substituted polyglycines) represent a class of bioinspired oligomers that have unique physical and structural properties. Here we report the construction of “extended peptoids” based on aromatic building blocks, in which the N-alkylaminoacetyl group of the peptoid backbone has been replaced by an N-alkylaminomethylbenzoyl spacer. Both meta- and para-bromomethylbenzoic acids were synthesized, providing access to a new class of peptoids. Further, inclusion of hydrophilic side chains confers water solubility to these compounds, showing that, like simple peptoids, extended peptoids add an extra dimension to synthetic polyamide oligomers with potential application in a variety of biological contexts.
April 9, 2007
Tetrahedron Letters
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by Rezai T, Yu B, Millhauser GL, Jacobson MP, Lokey RS
Little is known about the effect of conformation on passive membrane diffusion rates in small molecules. Evidence suggests that intramolecular hydrogen bonding may play a role by reducing the energetic cost of desolvating hydrogen bond donors, especially amide N-H groups. We set out to test this hypothesis by investigating the passive membrane diffusion characteristics of a series of cyclic peptide diastereomers based on the sequence cyclo[Leu-Leu-Leu-Leu-Pro-Tyr]. We identified two cyclic hexapeptide diastereomers based on this sequence, whose membrane diffusion rates differed by nearly two log units. Results of solution NMR studies and hydrogen/deuterium (H/D) exchange experiments showed that membrane diffusion rates correlated with the degree of intramolecular hydrogen bonding and H/D exchange rates. The most permeable diastereomer, cyclo[d-Leu-d-Leu-Leu-d-Leu-Pro-Tyr] (1), exhibited a passive membrane diffusion rate comparable to that of the orally available drug cyclosporine A.
March 1, 2006
Journal of the American Chemical Society
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