Cargando…

Impact of Selected Small-Molecule Kinase Inhibitors on Lipid Membranes

Small-molecule protein kinase inhibitors are used for the treatment of various diseases. Although their effect(s) on the respective kinase are generally quite well understood, surprisingly, their interaction with membranes is only barely investigated; even though these drugs necessarily come into co...

Descripción completa

Detalles Bibliográficos
Autores principales: Luck, Meike, Fischer, Markus, Werle, Maximilian, Scheidt, Holger A., Müller, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401620/
https://www.ncbi.nlm.nih.gov/pubmed/34451842
http://dx.doi.org/10.3390/ph14080746
_version_ 1783745594165035008
author Luck, Meike
Fischer, Markus
Werle, Maximilian
Scheidt, Holger A.
Müller, Peter
author_facet Luck, Meike
Fischer, Markus
Werle, Maximilian
Scheidt, Holger A.
Müller, Peter
author_sort Luck, Meike
collection PubMed
description Small-molecule protein kinase inhibitors are used for the treatment of various diseases. Although their effect(s) on the respective kinase are generally quite well understood, surprisingly, their interaction with membranes is only barely investigated; even though these drugs necessarily come into contact with the plasma and intracellular membranes. Using biophysical methods such as NMR, ESR, and fluorescence spectroscopy in combination with lipid vesicles, we studied the membrane interaction of the kinase inhibitors sunitinib, erlotinib, idelalisib, and lenvatinib; these drugs are characterized by medium log p values, a parameter reflecting the overall hydrophobicity of the molecules, which is one important parameter to predict the interaction with lipid membranes. While all four molecules tend to embed in a similar region of the lipid membrane, their presence has different impacts on membrane structure and dynamics. Most notably, sunitinib, exhibiting the lowest log p value of the four inhibitors, effectively influences membrane integrity, while the others do not. This shows that the estimation of the effect of drug molecules on lipid membranes can be rather complex. In this context, experimental studies on lipid membranes are necessary to (i) identify drugs that may disturb membranes and (ii) characterize drug–membrane interactions on a molecular level. Such knowledge is important for understanding the efficacy and potential side effects of respective drugs.
format Online
Article
Text
id pubmed-8401620
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-84016202021-08-29 Impact of Selected Small-Molecule Kinase Inhibitors on Lipid Membranes Luck, Meike Fischer, Markus Werle, Maximilian Scheidt, Holger A. Müller, Peter Pharmaceuticals (Basel) Article Small-molecule protein kinase inhibitors are used for the treatment of various diseases. Although their effect(s) on the respective kinase are generally quite well understood, surprisingly, their interaction with membranes is only barely investigated; even though these drugs necessarily come into contact with the plasma and intracellular membranes. Using biophysical methods such as NMR, ESR, and fluorescence spectroscopy in combination with lipid vesicles, we studied the membrane interaction of the kinase inhibitors sunitinib, erlotinib, idelalisib, and lenvatinib; these drugs are characterized by medium log p values, a parameter reflecting the overall hydrophobicity of the molecules, which is one important parameter to predict the interaction with lipid membranes. While all four molecules tend to embed in a similar region of the lipid membrane, their presence has different impacts on membrane structure and dynamics. Most notably, sunitinib, exhibiting the lowest log p value of the four inhibitors, effectively influences membrane integrity, while the others do not. This shows that the estimation of the effect of drug molecules on lipid membranes can be rather complex. In this context, experimental studies on lipid membranes are necessary to (i) identify drugs that may disturb membranes and (ii) characterize drug–membrane interactions on a molecular level. Such knowledge is important for understanding the efficacy and potential side effects of respective drugs. MDPI 2021-07-29 /pmc/articles/PMC8401620/ /pubmed/34451842 http://dx.doi.org/10.3390/ph14080746 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Luck, Meike
Fischer, Markus
Werle, Maximilian
Scheidt, Holger A.
Müller, Peter
Impact of Selected Small-Molecule Kinase Inhibitors on Lipid Membranes
title Impact of Selected Small-Molecule Kinase Inhibitors on Lipid Membranes
title_full Impact of Selected Small-Molecule Kinase Inhibitors on Lipid Membranes
title_fullStr Impact of Selected Small-Molecule Kinase Inhibitors on Lipid Membranes
title_full_unstemmed Impact of Selected Small-Molecule Kinase Inhibitors on Lipid Membranes
title_short Impact of Selected Small-Molecule Kinase Inhibitors on Lipid Membranes
title_sort impact of selected small-molecule kinase inhibitors on lipid membranes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401620/
https://www.ncbi.nlm.nih.gov/pubmed/34451842
http://dx.doi.org/10.3390/ph14080746
work_keys_str_mv AT luckmeike impactofselectedsmallmoleculekinaseinhibitorsonlipidmembranes
AT fischermarkus impactofselectedsmallmoleculekinaseinhibitorsonlipidmembranes
AT werlemaximilian impactofselectedsmallmoleculekinaseinhibitorsonlipidmembranes
AT scheidtholgera impactofselectedsmallmoleculekinaseinhibitorsonlipidmembranes
AT mullerpeter impactofselectedsmallmoleculekinaseinhibitorsonlipidmembranes