title: Predicting binding to p-glycoprotein by flexible receptor docking.
abstract: 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.
authors: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA. lena.dolgikh@ucsf.edu
authors: Elena
authors: E
authors: Dolghih
authors: Clifford
authors: C
authors: Bryant
authors: Adam R
authors: AR
authors: Renslo
authors: Matthew P
authors: MP
authors: Jacobson
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000378:metabolism*; D000465:Algorithms; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000378:metabolism; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D056004:Molecular Dynamics Simulation; D010599:Pharmacokinetics; D018583:Pliability; D011485:Protein Binding; D012372:ROC Curve
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015853:Cysteine Proteinase Inhibitors