Fragment-based drug nanoaggregation reveals drivers of self-assembly

• Published in: Nature communications Vol. 14; no. 1; p. 8340
• Main Authors: Chen, Chen, Wu, You, Wang, Shih-Ting, Berisha, Naxhije, Manzari, Mandana T., Vogt, Kristen, Gang, Oleg, Heller, Daniel A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-12-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 639/301/357/341; 639/925/357/354; Core-shell structure; Drug delivery; Drug development; Drug screening; Fragments; Humanities and Social Sciences; Hydrogen; Hydrogen bonding; Hydrogen bonds; Intracellular; multidisciplinary; NANOSCIENCE AND NANOTECHNOLOGY; Pharmacokinetics; Science; Science (multidisciplinary); Self-assembly
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-43560-0

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.