title: Binding of ACE-inhibitors to in vitro and patient-derived amyloid-β fibril models.
abstract: Currently, no drugs exist that can prevent or reverse Alzheimer's disease, a neurodegenerative disease associated with the presence, in the brain, of plaques that are composed of β-amyloid (Aβ) peptides. Recent studies suggest that angiotensin-converting enzyme (ACE) inhibitors, a set of drugs used to treat hypertension, may inhibit amyloid formation in vitro. In the present study, we investigate through computer simulations the binding of ACE inhibitors to patient-derived Aβ fibrils and contrast it with that of ACE inhibitors binding to in vitro generated fibrils. The binding affinities of the ACE inhibitors are compared with that of Congo red, a dye that is used to identify amyloid structures and that is known to be a weak inhibitor of Aβ aggregation. We find that ACE inhibitors have a lower binding affinity to the patient-derived fibrils than to in vitro generated ones. For patient-derived fibrils, their binding affinities are even lower than that of Congo red. Our observations raise doubts on the hypothesis that these drugs inhibit fibril formation in Alzheimer patients by interacting directly with the amyloids.
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, USA.
authors.forename: Manikanthan
authors.initials: M
authors.lastname: Bhavaraju
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, USA.
authors.forename: Malachi
authors.initials: M
authors.lastname: Phillips
authors.affiliation: Department of Biology, Langston University, Langston, Oklahoma 73050, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Bowman
authors.affiliation: Department of Chemistry, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autonoma de Mexico, Cuautitlán Izcalli, Estado de Mexico, 15740, Mexico.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Aceves-Hernandez
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, USA.
authors.forename: Ulrich H E
authors.initials: UH
authors.lastname: Hansmann
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D003224:Congo Red / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D016229:Amyloid beta-Peptides; D000806:Angiotensin-Converting Enzyme Inhibitors; D003224:Congo Red