Identification of novel functional inhibitors of acid sphingomyelinase.

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity...

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Autores principales:	Johannes Kornhuber, Markus Muehlbacher, Stefan Trapp, Stefanie Pechmann, Astrid Friedl, Martin Reichel, Christiane Mühle, Lothar Terfloth, Teja W Groemer, Gudrun M Spitzer, Klaus R Liedl, Erich Gulbins, Philipp Tripal
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bd25bf066ec3473fbd19d8571dd669db
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spelling	oai:doaj.org-article:bd25bf066ec3473fbd19d8571dd669db2021-11-18T06:46:55ZIdentification of novel functional inhibitors of acid sphingomyelinase.1932-620310.1371/journal.pone.0023852https://doaj.org/article/bd25bf066ec3473fbd19d8571dd669db2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21909365/?tool=EBIhttps://doaj.org/toc/1932-6203We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans.Johannes KornhuberMarkus MuehlbacherStefan TrappStefanie PechmannAstrid FriedlMartin ReichelChristiane MühleLothar TerflothTeja W GroemerGudrun M SpitzerKlaus R LiedlErich GulbinsPhilipp TripalPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 8, p e23852 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Johannes Kornhuber Markus Muehlbacher Stefan Trapp Stefanie Pechmann Astrid Friedl Martin Reichel Christiane Mühle Lothar Terfloth Teja W Groemer Gudrun M Spitzer Klaus R Liedl Erich Gulbins Philipp Tripal Identification of novel functional inhibitors of acid sphingomyelinase.
description	We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans.
format	article
author	Johannes Kornhuber Markus Muehlbacher Stefan Trapp Stefanie Pechmann Astrid Friedl Martin Reichel Christiane Mühle Lothar Terfloth Teja W Groemer Gudrun M Spitzer Klaus R Liedl Erich Gulbins Philipp Tripal
author_facet	Johannes Kornhuber Markus Muehlbacher Stefan Trapp Stefanie Pechmann Astrid Friedl Martin Reichel Christiane Mühle Lothar Terfloth Teja W Groemer Gudrun M Spitzer Klaus R Liedl Erich Gulbins Philipp Tripal
author_sort	Johannes Kornhuber
title	Identification of novel functional inhibitors of acid sphingomyelinase.
title_short	Identification of novel functional inhibitors of acid sphingomyelinase.
title_full	Identification of novel functional inhibitors of acid sphingomyelinase.
title_fullStr	Identification of novel functional inhibitors of acid sphingomyelinase.
title_full_unstemmed	Identification of novel functional inhibitors of acid sphingomyelinase.
title_sort	identification of novel functional inhibitors of acid sphingomyelinase.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/bd25bf066ec3473fbd19d8571dd669db
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Identification of novel functional inhibitors of acid sphingomyelinase.

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