Kleemiss, FlorianFlorianKleemiss0000-0002-3631-1535Justies, AileenAileenJustiesDuvinage, DanielDanielDuvinageWatermann, PatrickPatrickWatermannEhrke, EricEricEhrkeSugimoto, KunihisaKunihisaSugimotoFugel, MalteMalteFugelMalaspina, LorraineLorraineMalaspina0000-0002-8281-4264Dittmer, AnnekeAnnekeDittmerKleemiss, TorstenTorstenKleemissPuylaert, PimPimPuylaertKing, Nelly R.Nelly R.KingStaubitz, AnneAnneStaubitzTzschentke, Thomas M.Thomas M.TzschentkeDringen, RalfRalfDringenGrabowsky, SimonSimonGrabowsky0000-0002-3377-9474Beckmann, JensJensBeckmann2024-10-052024-10-052020-09-15https://boris-portal.unibe.ch/handle/20.500.12422/55927The 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.en500 - Science::570 - Life sciences; biology500 - Science::540 - Chemistryarticle10.48350/1506143293127410.1021/acs.jmedchem.0c00813