Fragment-based drug nanoaggregation reveals drivers of self-assembly

Chen Chen, You Wu, Shih-Ting Wang, Naxhije Berisha, Mandana T. Manzari, Kristen Vogt, Oleg Gang and Daniel A. Heller ()
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Chen Chen: Memorial Sloan Kettering Cancer Center
You Wu: Memorial Sloan Kettering Cancer Center
Shih-Ting Wang: Brookhaven National Laboratory
Naxhije Berisha: Memorial Sloan Kettering Cancer Center
Mandana T. Manzari: Memorial Sloan Kettering Cancer Center
Kristen Vogt: Memorial Sloan Kettering Cancer Center
Oleg Gang: Brookhaven National Laboratory
Daniel A. Heller: Memorial Sloan Kettering Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-43560-0

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