Discovery Chemistry, Gedeon Richter, PO Box 27, H-1475 Budapest, Hungary.
Future Med Chem. 2011 Mar;3(3):297-307. doi: 10.4155/fmc.10.276.
Due to its impact on multidrug resistance and pharmacokinetics P-glycoprotein (P-gp) has been identified as an important anti-target in pharmaceutical research. Recent publication of the mouse P-gp structure prompted us to build a new model for human P-gp and investigate its binding-site characteristics.
We developed and validated the human P-gp model that was used for induced-fit docking of experimentally characterized P-gp substrates. Residues located in the binding pocket are in good correlation with the results of side-directed mutagenesis studies. However, enrichment studies aimed at discriminating inhibitors and substrates from decoys resulted in only limited enrichments.
A mouse P-gp-based homology model might be useful when analyzing protein-ligand interactions of known human P-gp substrates if induced-fit effects are considered.
由于其对多药耐药性和药代动力学的影响，P-糖蛋白（P-gp）已被确定为药物研究中的一个重要的抗靶标。最近公布的小鼠 P-gp 结构促使我们构建了一个新的人类 P-gp 模型，并研究了其结合部位的特征。
我们开发并验证了人 P-gp 模型，该模型用于对经过实验表征的 P-gp 底物进行诱导契合对接。位于结合口袋中的残基与侧定向突变研究的结果具有很好的相关性。然而，旨在区分抑制剂和底物与诱饵的富集研究仅导致了有限的富集。
当分析已知的人 P-gp 底物的蛋白-配体相互作用时，如果考虑诱导契合效应，基于小鼠 P-gp 的同源模型可能是有用的。
