This work proposes a novel approach by which to consistently classify cysteine sites in proteins in terms of their reactivity toward dimethyl fumarate (DMF) and fumarate. Dimethyl fumarate-based drug products have been approved for use as oral treatments for psoriasis and relapsing-remitting multiple sclerosis. The adduction of DMF and its (re)active metabolites to certain cysteine residues in proteins is thought to underlie their effects. However, only a few receptors for these compounds have been discovered to date. Our approach takes advantage of the growing number of known DMF- and fumarate-sensitive proteins and sites to perform analyses by combining the concepts of network theory, for protein structure analyses, and machine-learning procedures. Wide-ranging and previously unforeseen variety is found in the analysis of the neighborhood composition (the first neighbors) of cysteine sites found in DMF- and fumarate-sensitive proteins. Furthermore, neighborhood composition has shown itself to be a network-type attribute that is endowed with remarkable predictive power when distinct classification algorithms are employed. In conclusion, when adopted in combination with other target identification/validation approaches, methods that are based on the analysis of cysteine site neighbors in proteins should provide useful information by which to decipher the mode of action of DMF-based drugs.
Analyzing Cysteine Site Neighbors in Proteins to Reveal Dimethyl Fumarate Targets
Rosa A. C.
First
;Benetti E.;Gallicchio M.;Boscaro V.;Cangemi L.;Dianzani C.;Miglio G.
Last
2019-01-01
Abstract
This work proposes a novel approach by which to consistently classify cysteine sites in proteins in terms of their reactivity toward dimethyl fumarate (DMF) and fumarate. Dimethyl fumarate-based drug products have been approved for use as oral treatments for psoriasis and relapsing-remitting multiple sclerosis. The adduction of DMF and its (re)active metabolites to certain cysteine residues in proteins is thought to underlie their effects. However, only a few receptors for these compounds have been discovered to date. Our approach takes advantage of the growing number of known DMF- and fumarate-sensitive proteins and sites to perform analyses by combining the concepts of network theory, for protein structure analyses, and machine-learning procedures. Wide-ranging and previously unforeseen variety is found in the analysis of the neighborhood composition (the first neighbors) of cysteine sites found in DMF- and fumarate-sensitive proteins. Furthermore, neighborhood composition has shown itself to be a network-type attribute that is endowed with remarkable predictive power when distinct classification algorithms are employed. In conclusion, when adopted in combination with other target identification/validation approaches, methods that are based on the analysis of cysteine site neighbors in proteins should provide useful information by which to decipher the mode of action of DMF-based drugs.File | Dimensione | Formato | |
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Rosa_et_al-2019-PROTEOMICS.pdf
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