The subcellular distribution of small molecules: a meta-analysis.
Summary of "The subcellular distribution of small molecules: a meta-analysis."
To explore the extent to which current knowledge about the organelle-targeting features of small molecules may be applicable toward 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 DrugBank and PubChem molecules, molecules with reported subcellular localizations were biased toward 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.
Department of Pharmaceutical Sciences, College of Pharmacy, and ‡Department of Statistics, University of Michigan , Ann Arbor, Michigan 48109, United States.
This article was published in the following journal.
Name: Molecular pharmaceutics
Medical and Biotech [MESH] Definitions
Works consisting of studies using a quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc. It is often an overview of clinical trials. It is usually called a meta-analysis by the author or sponsoring body and should be differentiated from reviews of literature.
Spectrometry, Mass, Matrix-assisted Laser Desorption-ionization
A mass spectrometric technique that is used for the analysis of large biomolecules. Analyte molecules are embedded in an excess matrix of small organic molecules that show a high resonant absorption at the laser wavelength used. The matrix absorbs the laser energy, thus inducing a soft disintegration of the sample-matrix mixture into free (gas phase) matrix and analyte molecules and molecular ions. In general, only molecular ions of the analyte molecules are produced, and almost no fragmentation occurs. This makes the method well suited for molecular weight determinations and mixture analysis.
Small Molecule Libraries
Large collections of small molecules (molecular weight about 600 or less), of similar or diverse nature which are used for high-throughput screening analysis of the gene function, protein interaction, cellular processing, biochemical pathways, or other chemical interactions.
Protein Array Analysis
Ligand-binding assays that measure protein-protein, protein-small molecule, or protein-nucleic acid interactions using a very large set of capturing molecules, i.e., those attached separately on a solid support, to measure the presence or interaction of target molecules in the sample.
Two-hybrid System Techniques
Screening techniques first developed in yeast to identify genes encoding interacting proteins. Variations are used to evaluate interplay between proteins and other molecules. Two-hybrid techniques refer to analysis for protein-protein interactions, one-hybrid for DNA-protein interactions, three-hybrid interactions for RNA-protein interactions or ligand-based interactions. Reverse n-hybrid techniques refer to analysis for mutations or other small molecules that dissociate known interactions.
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