The Subcellular Distribution of Small Molecules: A Meta-Analysis

Abstract

To explore the extent to which current knowledge about the organelle-targeting features of small molecules may be applicable towards controlling the accumulation and distribution of exogenous chemical agents inside cells, molecules with known subcellular localization properties (as reported in the scientific literature) were compiled into a single data set. This data set was compared to a reference data set of approved drug molecules derived from the DrugBank database, and to a reference data set of random organic molecules derived from the PubChem database. Cheminformatic analysis revealed that molecules with reported subcellular localizations were comparably diverse. However, the calculated physicochemical properties of molecules reported to accumulate in different organelles were markedly overlapping. In relation to the reference sets of Drug Bank and Pubchem molecules, molecules with reported subcellular localizations were biased towards larger, more complex chemical structures possessing multiple ionizable functional groups and higher lipophilicity. Stratifying molecules based on molecular weight revealed that many physicochemical properties trends associated with specific organelles were reversed in smaller vs. larger molecules. Most likely, these reversed trends are due to the different transport mechanisms determining the subcellular localization of molecules of different sizes. Molecular weight can be dramatically altered by tagging molecules with fluorophores or by incorporating organelle targeting motifs. Generally, in order to better exploit structure-localization relationships, subcellular targeting strategies would benefit from analysis of the biodistribution effects resulting from variations in the size of the molecules.

Guiding Drugs to Target‐Harboring Organelles: Stretching Drug‐Delivery to a Higher Level of Resolution

“…[50] Since dysfunctional lysosomes can lead to malignancy, these organelles may contain as yet unidentified molecular targets for antitumor agents.I na nother study the subcellular localizations of doxorubicin and daunorubicin and analogues derived from these two anthracyclines were determined in rat cardiomyoblasts. With additional data and application of Big Data analysis methods, [52] it should be possible to identify many more nuclear-directing chemical motifs in the future. These studies demonstrate that even subtle structural differences can have asignificant effect on the organelle preference of ad rug.…”

The Subcellular Distribution of Small Molecules: From Pharmacokinetics to Synthetic Biology

“…Current knowledge of the physiological properties and general principles of targeted delivery to the major intracellular organelles were summarized (Table 1). The criteria of article collection and the qualitative description of subcellular localization patterns were described in a separate paper ( 11 , accepted in Molecular Pharmaceutics). From the outset, it is noteworthy that most compounds were reported to localize within a single organelle, with few reports of compounds localized to multiple sites (Table 2).…”

“… Supporting information An excel database file with all the literature references and information of compounds with reported subcellular localizations or compounds from PubChem and DrugBank databases was deposited at the University of Michigan’s Deep Blue data repository and can be accessed through the following URL: http://hdl.handle.net/2027.42/84659 This data has been converted to tabular form and is also provided in the accompanying article 11 , under review in Molecular Pharmaceutics. …”

“…This data has been converted to tabular form and is also provided in the accompanying article 11 , under review in Molecular Pharmaceutics.…”

Hydrophobicity determines the fate of self-assembled fluorescent nanoparticles in cells

“…31,32 Studies have correlated these parameters to subcellular localization resulting in quantitative structure-activity decision rule models (QSAR). 31,[33][34][35] According to a decision-logic table, 35 the bola-oligomer should localize in the cytosol (potentially via protein binding), Golgi membranes and lipid droplets, because of the calculated log P value of 5.2 36 and the overall neutral charge of the bola-oligomer. The higher hydrophobicity in these cellular domains, compared to bulk water, and hydrophobic driven interaction with biomolecules would explain the emission blue-shift of the chromophore of the bola-oligomer.…”