Fragment-based drug nanoaggregation reveals drivers of self-assembly

Abstract

Self-assembled drug nanoaggregates are of interest due to their potential to form in cells, interfere with protein folding, or facilitate drug delivery approaches to improve the solubility, bioavailability, and pharmacokinetics. However, the physicochemical properties and molecular features of small molecules that mechanistically drive the formation of drug nanoparticles remain elusive. Therefore, the rational design of nanoaggregate-based carriers, and the prediction of intracellular aggregation based on drug structure, is still challenging. Inspired from fragment-based drug discovery, we systematically investigated self-assembly mechanisms using small molecule fragments in indocyanine-based nanoaggregates to identify the critical non-covalent molecular forces that contribute to self-assembly. We found that aromaticity and hydrogen bond acceptors and donors on fragments were essential for nanoparticle formation, suggesting the system is driven by both π-π stacking of the aromatic groups and hydrogen bonding. We applied fragment molecular feature analysis to a kinase inhibitor, a full-size clinical compound, and discovered that nanoparticle formability is intrinsically associated within the drug fragment substructures. We also found that these drug aggregates form core-shell structures but lack ordered internal packings and are amorphous in solution. These findings suggest that incorporation of molecular design features can address intracellular aggregation and pharmacologic or delivery challenges in conventional and fragment-based drug development processes.