Abstract |
The synthesis, characterization, biological activity, and toxicology of sila- ibuprofen, a silicon derivative of the most common nonsteroidal anti-inflammatory drug, is reported. The key improvements compared with ibuprofen are a four times higher solubility in physiological media and a lower melting enthalpy, which are attributed to the carbon- silicon switch. The improved solubility is of interest for postsurgical intravenous administration. A potential for pain relief is rationalized via inhibition experiments of cyclooxygenases I and II (COX-I and COX-II) as well as via a set of newly developed methods that combine molecular dynamics, quantum chemistry, and quantum crystallography. The binding affinity of sila- ibuprofen to COX-I and COX-II is quantified in terms of London dispersion and electrostatic interactions in the active receptor site. This study not only shows the potential of sila- ibuprofen for medicinal application but also improves our understanding of the mechanism of action of the inhibition process.
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Authors | Florian Kleemiss, Aileen Justies, Daniel Duvinage, Patrick Watermann, Eric Ehrke, Kunihisa Sugimoto, Malte Fugel, Lorraine A Malaspina, Anneke Dittmer, Torsten Kleemiss, Pim Puylaert, Nelly R King, Anne Staubitz, Thomas M Tzschentke, Ralf Dringen, Simon Grabowsky, Jens Beckmann |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 63
Issue 21
Pg. 12614-12622
(11 12 2020)
ISSN: 1520-4804 [Electronic] United States |
PMID | 32931274
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anti-Inflammatory Agents, Non-Steroidal
- Carbon
- Cyclooxygenase 1
- Cyclooxygenase 2
- Ibuprofen
- Silicon
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Topics |
- Anti-Inflammatory Agents, Non-Steroidal
(chemical synthesis, chemistry, metabolism)
- Binding Sites
- Carbon
(chemistry)
- Catalytic Domain
- Cyclooxygenase 1
(chemistry, metabolism)
- Cyclooxygenase 2
(chemistry, metabolism)
- Humans
- Ibuprofen
(chemistry, metabolism)
- Molecular Conformation
- Molecular Dynamics Simulation
- Protein Binding
- Quantum Theory
- Silicon
(chemistry)
- Static Electricity
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