TY - JOUR T1 - Exhaustive Sampling of Docking Poses Reveals Binding Hypotheses for Propafenone Type Inhibitors of P-Glycoprotein A1 - Klepsch, Freya A1 - Chiba, Peter A1 - Ecker, Gerhard F. Y1 - 2011/05/12 N2 - Author Summary A major reason for the failure of cancer, antibiotic and antiviral therapies is the development of multidrug resistance (MDR). P-glycoprotein (P-gp), an ATP-dependent transport protein located in the membrane of epithelial cells of the kidney, liver, pancreas, colon and the blood-brain barrier, has been linked to the export of a broad variety of xenotoxins. Overexpression of P-gp leads to extrusion of therapeutic drugs and therefore triggers MDR. Thus, identification of potential P-gp inhibitors represents a promising concept for treatment of multiresistant tumours. However, due to lack of high resolution structural information and the polyspecific ligand recognition pattern only very limited information is available on the molecular basis of ligand/transporter interaction. Within this study we characterized the propafenone binding site of P-gp by docking a set of derivatives with known SAR into homology models of P-gp which represent both the apo and the nucleotide-bound state. Poses retrieved are in accordance with results from previous photoaffinity labeling studies and thus pave the way for structure-based in silico screening approaches. JF - PLOS Computational Biology JA - PLOS Computational Biology VL - 7 IS - 5 UR - https://doi.org/10.1371/journal.pcbi.1002036 SP - e1002036 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pcbi.1002036 ER -