Abstract

P-glycoprotein (P-gp, MDR1), one of ATP-binding cassette transporters, may confer tumor cells cross-resistance to chemotherapeutics. A large amount of P-gp inhibitors were designed to inhibit the multidrug resistance (MDR) feature of P-gp. However, no sufficient researches were reported to explore the correlation between binding capacity and drug property by experiment. Without particular drug property found to inhibit the MDR feature of P-gp, the orientation of drug design is indefinite. In this work, 10 representative cancer drugs with various properties are used to bind with P-gp by molecular dynamics simulation. Binding free energy between P-gp and 10 drugs ranges −139 to −253 kJ/mol. It reveals that the promiscuity nature of P-gp is in light of the similar binding free energy in separate P-gp-ligand binding systems. The binding effect of P-gp and drugs correlates well with the size of drugs and has no apparent correlation with the polarity of each drug. The key reason is that van der Waal’s interaction occupies most of the total binding free energy, and it is led by the number of atoms in the drugs. Two transmembrane segments (TM6 and TM12) and three types of amino acids (PHE, MET, and GLN) are vital in binding drugs with van der Waal’s energy, which evident the influence between binding stability and size of drugs. This work provides the cause and theoretical basis for the promiscuity nature of P-gp.

Communicated by Ramaswamy H. Sarma

摘要

P-糖蛋白 (P-gp, MDR1) 是一种 ATP 结合盒转运蛋白，可赋予肿瘤细胞对化疗药物的交叉耐药性。大量的 P-gp 抑制剂被设计用来抑制 P-gp 的多药耐药 (MDR) 特征。然而，没有足够的研究报告通过实验探索结合能力与药物性质之间的相关性。如果没有发现抑制 P-gp 的 MDR 特征的特定药物特性，药物设计的方向是不确定的。在这项工作中，10 种具有各种特性的代表性抗癌药物通过分子动力学模拟与 P-gp 结合。P-gp 和 10 种药物之间的结合自由能范围为 -139 至 -253 kJ/mol。它揭示了 P-gp 的混杂性质是由于在单独的 P-gp-配体结合系统中具有相似的结合自由能。P-gp与药物的结合作用与药物的大小有很好的相关性，与每种药物的极性没有明显的相关性。关键的原因是范德华相互作用占据了总结合自由能的大部分，它由药物中的原子数主导。两个跨膜片段（TM6 和 TM12）和三种类型的氨基酸（PHE、MET 和 GLN）对于以范德华能量结合药物至关重要，这表明结合稳定性和药物大小之间的影响。这项工作为P-gp的滥交性质提供了原因和理论基础。两个跨膜片段（TM6 和 TM12）和三种类型的氨基酸（PHE、MET 和 GLN）对于以范德华能量结合药物至关重要，这表明结合稳定性和药物大小之间的影响。这项工作为P-gp的滥交性质提供了原因和理论基础。两个跨膜片段（TM6 和 TM12）和三种类型的氨基酸（PHE、MET 和 GLN）对于以范德华能量结合药物至关重要，这表明结合稳定性和药物大小之间的影响。这项工作为P-gp的滥交性质提供了原因和理论基础。

由 Ramaswamy H. Sarma 交流