Abstract |
The urokinase plasminogen activator (uPA) plays a critical role in tumor cell invasion and migration and is a promising antimetastasis target. 6-Substituted analogues of 5-N,N-(hexamethylene)amiloride (HMA) are potent and selective uPA inhibitors that lack the diuretic and antikaliuretic properties of the parent drug amiloride. However, the compounds display pronounced selectivity for human over mouse uPA, thus confounding interpretation of data from human xenograft mouse models of cancer. Here, computational and experimental findings reveal that residue 99 is a key contributor to the observed species selectivity, whereby enthalpically unfavorable expulsion of a water molecule by the 5-N,N-hexamethylene ring occurs when residue 99 is Tyr (as in mouse uPA). Analogue 7 lacking the 5-N,N-hexamethylene ring maintained similar water networks when bound to human and mouse uPA and displayed reduced selectivity, thus supporting this conclusion. The study will guide further optimization of dual-potent human/mouse uPA inhibitors from the amiloride class as antimetastasis drugs.
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Authors | Nehad S El Salamouni, Benjamin J Buckley, Longguang Jiang, Mingdong Huang, Marie Ranson, Michael J Kelso, Haibo Yu |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 65
Issue 3
Pg. 1933-1945
(02 10 2022)
ISSN: 1520-4804 [Electronic] United States |
PMID | 34898192
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Enzyme Inhibitors
- Water
- 5-(N,N-hexamethylene)amiloride
- Amiloride
- Urokinase-Type Plasminogen Activator
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Topics |
- Amiloride
(analogs & derivatives, chemistry, metabolism)
- Animals
- Enzyme Inhibitors
(chemistry, metabolism)
- Humans
- Mice
- Molecular Docking Simulation
- Molecular Dynamics Simulation
- Molecular Structure
- Mutation
- Protein Binding
- Species Specificity
- Thermodynamics
- Urokinase-Type Plasminogen Activator
(antagonists & inhibitors, genetics, metabolism)
- Water
(chemistry)
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