Journal Article

Predicting Binding to P-Glycoprotein by Flexible Receptor Docking

Dolghih, Elena, Jacobson, Matthew P., Bryant, Clifford, Renslo, Adam R.

2011

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Algorithms / Animals / ATP Binding Cassette Transporter, Sub-Family B / ATP-Binding Cassette, Sub-Family B, Member 1 - chemistry / ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism / Binding Sites / Biology / Blood-brain barrier / Cancer / Cell Line / Cell receptors / Cysteine Proteinase Inhibitors - chemistry / Cysteine Proteinase Inhibitors - metabolism / Dogs / Drug Discovery / Glycoproteins / Humans / Ligands / Metabolites / Methods / Mice / Molecular Dynamics Simulation / Pharmacokinetics / Physiological aspects / Pliability / Protein Binding / Proteins / ROC Curve / Tumors