Almeida Eduardo R, Goliatt Priscila V Z Capriles, Dos Santos Hélio F, Picaud Fabien
Núcleo de Estudos em Química Computacional (NEQC), Departamento de Química, ICE, Universidade Federal de Juiz de Fora (UFJF), Campus Universitário, Martelos, Juiz de Fora, MG 36036-330, Brazil.
Laboratoire de Nanomédecine, Imagerie et Thérapeutiques, EA 4662, Université de Franche-Comté, Centre Hospitalier Universitaire de Besançon, 16 route de Gray, 25030 Besançon cedex, France.
J Chem Inf Model. 2023 Oct 9;63(19):6141-6155. doi: 10.1021/acs.jcim.3c00943. Epub 2023 Sep 26.
Breast cancer is one of the most frequent modalities of cancer worldwide, with notable mortality. The medication based on platinum drugs (cisplatin (cddp), carboplatin (cpx), and oxaliplatin (oxa)) is a conventional chemotherapy despite severe side effects and the development of drug resistance. In order to provide a deeper molecular description of the influx and efflux processes of platinum drugs through breast cancer tissues, this study focuses on molecular dynamics (MD) simulations of the passive translocation process through a realistic plasma membrane prototype of human breast cancer cell (c_memb). The results showed that the permeation events were mainly mediated by neutral lipids (DOPC, DOPE, and cholesterol), producing a low and temporary membrane deformation. The drug insertion in the region of polar heads was the most favorable stage of the translocation mechanism, especially for cddp and oxa with potential wells of -8.6 and -9.8 kcal mol, respectively. However, the potentials of mean force (PMF) revealed unfavorable kinetics for the permeation of these drugs through lipid tails, with energy barriers of 28.3 (cddp), 32.2 (cpx), and 30.4 kcal mol (oxa). The low permeability coefficients () of cpx and oxa, which were 3 and 1 orders of magnitude inferior than for cddp, resulted from the high energy barriers for their traslocation processes through the membrane. The obtained results provide a more accurate picture of the permeation of Pt(II)-based drugs through breast cancer cells, which may be relevant for the design and evaluation of new platinum complexes.
乳腺癌是全球最常见的癌症类型之一，死亡率显著。基于铂类药物（顺铂（cddp）、卡铂（cpx）和奥沙利铂（oxa））的药物是一种传统化疗方法，尽管存在严重的副作用和耐药性问题。为了更深入地从分子层面描述铂类药物在乳腺癌组织中的流入和流出过程，本研究聚焦于通过人乳腺癌细胞（c_memb）的真实质膜原型进行被动转运过程的分子动力学（MD）模拟。结果表明，渗透事件主要由中性脂质（二油酰磷脂酰胆碱（DOPC）、二油酰磷脂酰乙醇胺（DOPE）和胆固醇）介导，产生低程度且短暂的膜变形。药物插入极性头部区域是转运机制中最有利的阶段，特别是对于顺铂和奥沙利铂，其势能阱分别为 -8.6 和 -9.8 千卡/摩尔。然而，平均力势能（PMF）显示这些药物通过脂质尾部渗透的动力学不利，能量势垒分别为 28.3（顺铂）、32.2（卡铂）和 30.4 千卡/摩尔（奥沙利铂）。卡铂和奥沙利铂的低渗透系数（）比顺铂低 3 个和 1 个数量级，这是由于它们通过膜的转运过程存在高能量势垒所致。所得结果为基于 Pt(II) 的药物透过乳腺癌细胞的渗透提供了更准确的描述，这可能与新型铂配合物的设计和评估相关。
