An in Silico Approach to Reveal the Nanodisc Formulation of Doxorubicin.
An in Silico Approach to Reveal the Nanodisc Formulation of Doxorubicin.
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揭示阿霉素纳米圆盘配方的计算机方法
DOI：
10.3389/fbioe.2022.859255
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发表时间：
2022
影响因子：
5.7
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Xu D;Chen X;Chen Z;Lv Y;Li Y;Li S;Xu W;Mo Y;Wang X;Chen Z;Chen T;Wang T;Wang Z;Wu M;Wang J
通过分子动力学 (MD) 模拟研究了游离阿霉素 (DOX) 和 DOX 缀合脂质前药分子的纳米盘 (ND) 制剂的分子动力学行为。我们揭示了配方设计如何影响 ND 组装体的药物释放曲线和构象稳定性。我们的模拟结果表明，由于 DOX 附着在脂质表面的不利方向，加载在 ND 系统中的游离 DOX 分子经历了快速解离。研究发现，DOX 倾向于与较高药物量形成聚集体。相反，掺入 ND 制剂中的脂化 DOX-前药表现出足够的 ND 构象稳定性。载药量取决于DOX前药上接枝的脂质分子的类型，NDs固定区域的载药量遵循以下顺序：DOX-BMPH-MP > DOX-BMPH-TC > DOX-BMPH-PTE。为了进一步了解不同类型脂化控制的 ND 制剂的动态特性，我们研究了 ND 组分的构象变化、分子间相互作用、溶剂可及表面积和单个 MSP1 残基的灵活性。我们发现负载 DOX 前药的 ND 组装体的整体构象稳定性受到 DOX 前药的分子灵活性和脂化形式的影响。我们还发现，随着 ND 上数量的增加，DOX 前药的自发自聚集可以降低膜的流动性并增强 ND 制剂的构象稳定性。
Molecular dynamic behaviors of nanodisc (ND) formulations of free doxorubicin (DOX) and DOX conjugated lipid prodrug molecules were investigated by molecular dynamics (MD) simulations. We have unveiled how formulation design affects the drug release profile and conformational stability of ND assemblies. Our simulation results indicate that free DOX molecules loaded in the ND system experienced rapid dissociation due to the unfavorable orientation of DOX attached to the lipid surface. It is found that DOX tends to form aggregates with higher drug quantities. In contrast, lipidated DOX-prodrugs incorporated in ND formulations exhibited sufficient ND conformational stability. The drug loading capacity is dependent on the type of lipid molecules grafted on the DOX-prodrug, and the drug loading quantities in a fixed area of NDs follow the order: DOX-BMPH-MP > DOX-BMPH-TC > DOX-BMPH-PTE. To gain further insight into the dynamic characteristics of ND formulations governed by different kinds of lipidation, we investigated the conformational variation of ND components, intermolecular interactions, the solvent accessible surface area, and individual MSP1 residue flexibility. We found that the global conformational stability of DOX-prodrug-loaded ND assemblies is influenced by the molecular flexibility and lipidated forms of DOX-prodrug. We also found that the spontaneous self-aggregation of DOX-prodrugs with increasing quantities on ND could reduce the membrane fluidity and enhance the conformational stability of ND formulations.