Journal
MOLECULAR PHARMACEUTICS
Volume 16, Issue 8, Pages 3350-3360Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.8b01301
Keywords
molecular imaging; in silico modeling; pharmacokinetics; theranostics
Funding
- University of Wisconsin MD Ph.D. program [T32 GM008692]
- NIH [R01NS75995]
- Headrush Brain Tumor Research Professorship
- Schapiro Research Fund
- NCI [R01-15880]
- Roger Loff Memorial Fund Farming against Brain Cancer
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Alkylphosphocholine (APC) analogs are a novel class of broad-spectrum tumor-targeting agents that can be used for both diagnosis and treatment of cancer. The potential for clinical translation for APC analogs will strongly depend on their pharmacokinetic (PK) profiles. The aim of this work was to understand how the chemical structures of various APC analogs impact binding and PK. To achieve this aim, we performed in silico docking analysis, in vitro and in vivo partitioning experiments, and in vivo PK studies. Our results have identified 7 potential high-affinity binding sites of these compounds on human serum albumin (HSA) and suggest that the size of the functional group directly influences the albumin binding, partitioning, and PK. Namely, the bulkier the functional groups, the weaker the agent binds to albumin, the more the agent partitions onto lipoproteins, and the less time the agent spends in circulation. The results of these experiments provide novel molecular insights into the binding, partitioning, and PK of this class of compounds and similar molecules as well as suggest pharmacological strategies to alter their PK profiles. Importantly, our methodology may provide a way to design better drugs by better characterizing the PK profile for lead compound optimization.
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