title: Assessing gastric toxicity of xanthone derivatives of anti-inflammatory activity using simulation and experimental approaches.
abstract: Xanthones are tricyclic compounds of natural or synthetic origin exhibiting a broad spectrum of therapeutic activities. Three synthetic xanthone derivatives (KS1, KS2, and KS3) with properties typical for nonsteroidal anti-inflammatory drugs (NSAID) were objects of the presented model study. NSAIDs are in common use however; several of them exhibit gastric toxicity predominantly resulting from their direct interactions with the outermost lipid layer of the gastric mucosa that impair its hydrophobic barrier property. Among the studied xanthones, gastric toxicity of only KS2 has been determined in previous pharmacological studies, and it is low. In this study, carried out using X-ray diffraction and computer simulation, a palmitoyloleoylphosphatidylcholine-cholesterol bilayer (POPC-Chol) was used as a model of a hydrophobic layer of lipids protecting gastric mucosa as POPC and Chol are the main lipids in human mucus. X-ray diffraction data were used to validate the computer model. The aim of the study was to assess potential gastric toxicity of the xanthones by analysing their atomic level interactions with lipids, ions, and water in the lipid bilayer and their effect on the bilayer physicochemical properties. The results show that xanthones have small effect on the bilayer properties except for its rigidity whereas their interactions with water, ions, and lipids depend on their protonation state and for a given state, are similar for all the xanthones. As gastric toxicity of KS2 is low, based on MD simulations one can predict that toxicity of KS1 and KS3 is also low.
authors.affiliation: Department of Computational Biophysics and Bioinformatics, Jagiellonian University, Krakow, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Markiewicz
authors.affiliation: Department of Radioligands, Jagiellonian University, Krakow, Poland.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Librowski
authors.affiliation: Department of Radioligands, Jagiellonian University, Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Lipkowska
authors.affiliation: Department of Crystal Chemistry and Crystal Physics, Jagiellonian University, Krakow, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Serda
authors.affiliation: Department of Computational Biophysics and Bioinformatics, Jagiellonian University, Krakow, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Baczynski
authors.affiliation: Department of Computational Biophysics and Bioinformatics, Jagiellonian University, Krakow, Poland. Electronic address: marta.pasenkiewicz-gierula@uj.edu.pl.
authors.forename: Marta
authors.initials: M
authors.lastname: Pasenkiewicz-Gierula
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000633:toxicity; D002784:Cholesterol; D003198:Computer Simulation; D005753:Gastric Mucosa / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D008051:Lipid Bilayers; D008954:Models, Biological; D010713:Phosphatidylcholines; D044004:Xanthones / Q000494:pharmacology / Q000633:toxicity*
chemical_list: D000893:Anti-Inflammatory Agents; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D044004:Xanthones; D002784:Cholesterol; C028694:1-palmitoyl-2-oleoylphosphatidylcholine
keywords: Gastric mucosa; Hydrogen bonds; Hydrophobic barrier; Lipid bilayer; MD simulation