Fragment-based drug nanoaggregation reveals drivers of self-assembly.
Fragment-based drug nanoaggregation reveals drivers of self-assembly.
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基于片段的药物纳米聚集揭示了自组装的驱动因素。
DOI：
10.1038/s41467-023-43560-0
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发表时间：
2023-12-14
影响因子：
16.6
通讯作者：
Heller, Daniel A.
中科院分区：
文献类型：
--
作者：
Chen, Chen;Wu, You;Wang, Shih-Ting;Berisha, Naxhije;Manzari, Mandana T.;Vogt, Kristen;Gang, Oleg;Heller, Daniel A.
药物纳米聚集体是在药物筛选工作期间可能有害地导致假阳性结果的颗粒，但是可选地，当开发用于药物递送目的时，它们可以用于改善药代动力学。然而，驱动纳米聚集体形成的分子的结构特征仍然难以捉摸，并且细胞内聚集的预测和基于纳米聚集体的载体的合理设计仍然具有挑战性。我们研究纳米聚集体的自组装机制，使用小分子片段，以确定关键的分子力，有助于自组装。我们发现，芳香族基团和氢键受体/供体是必不可少的纳米聚集体的形成，这表明π-π堆积和氢键是纳米聚集体的驱动程序。我们将结构-组装-关系分析应用于药物索拉非尼，并发现纳米聚集体的形成可以完全使用药物片段子结构来预测。我们还发现，药物纳米聚集体稳定在一个无定形的核-壳结构。这些研究结果表明，合理的设计可以解决细胞内聚集和药理学/交付的挑战，在传统的和基于片段的药物开发过程。药物纳米聚集体可用于改善药物的药代动力学，当开发用于药物递送时，然而，驱动纳米聚集体形成的分子的结构特征仍然难以捉摸。在这里，作者使用小分子片段研究纳米聚集体自组装机制，以确定有助于自组装的关键分子力，即芳香族基团和氢键受体/供体。
Drug nanoaggregates are particles that can deleteriously cause false positive results during drug screening efforts, but alternatively, they may be used to improve pharmacokinetics when developed for drug delivery purposes. The structural features of molecules that drive nanoaggregate formation remain elusive, however, and the prediction of intracellular aggregation and rational design of nanoaggregate-based carriers are still challenging. We investigate nanoaggregate self-assembly mechanisms using small molecule fragments to identify the critical molecular forces that contribute to self-assembly. We find that aromatic groups and hydrogen bond acceptors/donors are essential for nanoaggregate formation, suggesting that both π-π stacking and hydrogen bonding are drivers of nanoaggregation. We apply structure-assembly-relationship analysis to the drug sorafenib and discover that nanoaggregate formation can be predicted entirely using drug fragment substructures. We also find that drug nanoaggregates are stabilized in an amorphous core-shell structure. These findings demonstrate that rational design can address intracellular aggregation and pharmacologic/delivery challenges in conventional and fragment-based drug development processes. Drug nanoaggregates could be used to improve drug pharmacokinetics when developed for drug delivery, however, the structural features of molecules that drive nanoaggregate formation remain elusive. Here, the authors investigate nanoaggregate self-assembly mechanisms using small molecule fragments to identify the critical molecular forces that contribute to self-assembly, namely aromatic groups and hydrogen bond acceptors/donors.
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影响因子：
17.1
作者：
Anchordoquy TJ;Barenholz Y;Boraschi D;Chorny M;Decuzzi P;Dobrovolskaia MA;Farhangrazi ZS;Farrell D;Gabizon A;Ghandehari H;Godin B;La-Beck NM;Ljubimova J;Moghimi SM;Pagliaro L;Park JH;Peer D;Ruoslahti E;Serkova NJ;Simberg D
通讯作者：
Simberg D
影响因子：
4.6
作者：
Hong H;Akbari A;Wu J
通讯作者：
Wu J
影响因子：
4
作者：
Duan D;Torosyan H;Elnatan D;McLaughlin CK;Logie J;Shoichet MS;Agard DA;Shoichet BK
通讯作者：
Shoichet BK
影响因子：
3.3
作者：
Ghosh, Rikhia;Banerjee, Saikat;Bagchi, Biman
通讯作者：
Bagchi, Biman
影响因子：
2.9
作者：
Grein, F
通讯作者：
Grein, F