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.
@article{osti_2337597,
author = {Chen, Chen and Wu, You and Wang, Shih-Ting and Berisha, Naxhije and Manzari, Mandana T. and Vogt, Kristen and Gang, Oleg and Heller, Daniel A.},
title = {Fragment-based drug nanoaggregation reveals drivers of self-assembly},
annote = {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.},
doi = {10.1038/s41467-023-43560-0},
url = {https://www.osti.gov/biblio/2337597},
journal = {Nature Communications},
issn = {ISSN 2041-1723},
number = {1},
volume = {14},
place = {United States},
publisher = {Nature Publishing Group},
year = {2023},
month = {12}}
Brookhaven National Laboratory (BNL), Upton, NY (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); USDOE Laboratory Directed Research and Development (LDRD) Program; USDOE Office of Science (SC), Biological and Environmental Research (BER); National Science Foundation (NSF); National Institutes of Health (NIH); American Cancer Society (ACS)
DiFabio, Jonathan; Chodankar, Shirish; Pjerov, Sal
PROCEEDINGS OF THE 12TH INTERNATIONAL CONFERENCE ON SYNCHROTRON RADIATION INSTRUMENTATION – SRI2015, AIP Conference Proceedingshttps://doi.org/10.1063/1.4952872