title: Screening of fibrillogenesis inhibitors of β2-microglobulin: integrated strategies by mass spectrometry capillary electrophoresis and in silico simulations.
abstract: The challenging search of ligands for the amyloidogenic protein β(2)-microglobulin led us to set up an integrated strategy that combines analytical techniques and molecular modelling. Using a chemical library composed of 90 sulphonated molecules and a novel MS screening approach, we initially single out a few new binders. To check for anti-amyloid activity, the best hit obtained was thoroughly studied by docking analysis, affinity and refolding experiments by capillary electrophoresis and in vitro fibrillogenesis Thioflavin T test. Correlative analysis of the overall results obtained from the MS screening led to develop an equation able to identify the key factors of the affinity for β(2)-microglobulin and to predict the affinity for novel derivatives. The proposed equation was then used for a virtual screening of a large compound database. Studies on the new hit thus retrieved confirm the predictive potential of both the equation on affinity and of docking analysis on anti-amyloid activity.
authors.affiliation: Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Regazzoni
authors.forename: Raffaella
authors.initials: R
authors.lastname: Colombo
authors.forename: Laura
authors.initials: L
authors.lastname: Bertoletti
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Aldini
authors.forename: Massimo
authors.initials: M
authors.lastname: Serra
authors.forename: Marina
authors.initials: M
authors.lastname: Carini
authors.forename: Roberto Maffei
authors.initials: RM
authors.lastname: Facino
authors.forename: Sofia
authors.initials: S
authors.lastname: Giorgetti
authors.forename: Monica
authors.initials: M
authors.lastname: Stoppini
authors.forename: Gabriele
authors.initials: G
authors.lastname: Caccialanza
authors.forename: Ersilia
authors.initials: E
authors.lastname: De Lorenzi
mesh_terms: D004353:Drug Evaluation, Preclinical / Q000379:methods*; D019075:Electrophoresis, Capillary / Q000379:methods*; D008024:Ligands; D013058:Mass Spectrometry / Q000379:methods*; D008958:Models, Molecular; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries / Q000378:metabolism / Q000494:pharmacology; D018511:Systems Integration; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D054852:Small Molecule Libraries; D001613:beta 2-Microglobulin