Theory Department, Laboratory for Cheminformatics, National Institute of Chemistry, 1000 Ljubljana, Slovenia.
Jožef Stefan International Postgraduate School, 1000 Ljubljana, Slovenia.
Int J Mol Sci. 2020 Jun 5;21(11):4058. doi: 10.3390/ijms21114058.
The ABCB1 transporter also known as P-glycoprotein (P-gp) is a transmembrane protein belonging to the ATP binding cassette super-family of transporters; it is a xenobiotic efflux pump that limits intracellular drug accumulation by pumping the compounds out of cells. P-gp contributes to a decrease of toxicity and possesses broad substrate specificity. It is involved in the failure of numerous anticancer and antiviral chemotherapies due to the multidrug resistance (MDR) phenomenon, where it removes the chemotherapeutics out of the targeted cells. Understanding the details of the ligand-P-gp interaction is therefore crucial for the development of drugs that might overcome the MRD phenomenon and for obtaining a more effective prediction of the toxicity of certain compounds. In this work, an in silico modeling was performed using homology modeling and molecular docking methods with the aim of better understanding the ligand-P-gp interactions. Based on different mouse P-gp structural templates from the PDB repository, a 3D model of the human P-gp (P-gp) was constructed by means of protein homology modeling. The homology model was then used to perform molecular docking calculations on a set of thirteen compounds, including some well-known compounds that interact with P-gp as substrates, inhibitors, or both. The sum of ranking differences (SRD) was employed for the comparison of the different scoring functions used in the docking calculations. A consensus-ranking scheme was employed for the selection of the top-ranked pose for each docked ligand. The docking results showed that a high number of π interactions, mainly π-sigma, π-alkyl, and π-π type of interactions, together with the simultaneous presence of hydrogen bond interactions contribute to the stability of the ligand-protein complex in the binding site. It was also observed that some interacting residues in P-gp are the same when compared to those observed in a co-crystallized ligand (PBDE-100) with mouse P-gp (PDB ID: 4XWK). Our in silico approach is consistent with available experimental results regarding P-gp efflux transport assay; therefore it could be useful in the prediction of the role of new compounds in systemic toxicity.
ABCB1 转运体也称为 P-糖蛋白（P-gp），是一种属于 ATP 结合盒超家族转运体的跨膜蛋白；它是一种外源性排出泵，通过将化合物泵出细胞来限制细胞内药物积累。P-gp 有助于降低毒性，并具有广泛的底物特异性。由于多药耐药（MDR）现象，它将化疗药物从靶细胞中排出，导致许多抗癌和抗病毒化疗失败。因此，了解配体-P-gp 相互作用的细节对于开发可能克服 MDR 现象的药物以及更有效地预测某些化合物的毒性至关重要。在这项工作中，使用同源建模和分子对接方法进行了计算建模，目的是更好地理解配体-P-gp 相互作用。基于来自 PDB 存储库的不同小鼠 P-gp 结构模板，通过蛋白质同源建模构建了人类 P-gp（P-gp）的 3D 模型。然后，使用同源模型对一组 13 种化合物进行了分子对接计算，其中包括一些与 P-gp 作为底物、抑制剂或两者相互作用的知名化合物。用于比较对接计算中使用的不同评分函数的总和排序差异（SRD）。对于每个对接配体，采用共识排序方案选择排名最高的构象。对接结果表明，大量的π相互作用，主要是π-σ、π-烷基和π-π 类型的相互作用，以及氢键相互作用的同时存在，有助于配体-蛋白质复合物在结合部位的稳定性。还观察到，与与小鼠 P-gp（PDB ID：4XWK）共结晶的配体（PBDE-100）相比，P-gp 中存在一些相同的相互作用残基。我们的计算方法与 P-gp 外排转运测定的可用实验结果一致；因此，它可用于预测新化合物在全身毒性中的作用。
