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A Combined High‐Resolution Mass Spectrometric and in silico Approach for the Characterisation of Small Ligands of β 2 ‐Microglobulin
Author(s) -
Regazzoni Luca,
Bertoletti Laura,
Vistoli Giulio,
Colombo Raffaella,
Aldini Giancarlo,
Serra Massimo,
Carini Marina,
Caccialanza Gabriele,
De Lorenzi Ersilia
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000082
Subject(s) - fibrillogenesis , in silico , chemistry , beta 2 microglobulin , amyloid (mycology) , small molecule , amyloidosis , computational biology , mass spectrometry , high resolution , amyloid fibril , molecule , biochemistry , fibril , biophysics , amyloid β , chromatography , biology , medicine , organic chemistry , pathology , inorganic chemistry , remote sensing , disease , immunology , gene , geology
β 2 ‐Microglobulin (β 2 ‐m) is a protein responsible for a severe complication of long‐term hemodialysis, known as dialysis‐related amyloidosis, in which initial β 2 ‐m misfolding leads to amyloid fibril deposition, mainly in the skeletal tissue. Whereas much attention is paid to understanding the complex mechanism of amyloid formation, the evaluation of small molecules that may bind β 2 ‐m and possibly inhibit the aggregation process is still largely unexplored mainly because the protein lacks a specific active site. Based on our previous findings, we selected a pilot set of sulfonated molecules that are known to either bind or not to the protein, including binders that are anti‐amyloidogenic. We show how a complementary approach, using high‐resolution mass spectrometry and in silico studies, can offer rapid and precise information on affinity, as well as insight into the structural requisites that favour or disfavour the inhibitory activity. Overall, this approach can be used for predictive purposes and for a rapid screening of fibrillogenesis inhibitors.