Alzheimer's disease (AD) is a devastating neurological disorder characterized by the pathological accumulation of macromolecular Aβ and tau leading to neuronal death. Drugs approved to treat AD may ameliorate disease symptoms, however, no curative treatment exists. Aβ peptides were discovered to be substrates of adenosine triphosphate-(ATP)-binding cassette (ABC) transporters. Activators of these membrane-bound efflux proteins that promote binding and/or translocation of Aβ could revolutionize AD medicine. The knowledge about ABC transporter activators is very scarce, however, the few molecules that were reported contain substructural features of multitarget (pan-)ABC transporter inhibitors. A cutting-edge strategy to obtain new drug candidates is to explore and potentially exploit the recently proposed multitarget binding site of pan-ABC transporter inhibitors as anchor point for the development of innovative activators to promote Aβ clearance from the brain. Molecular associations between functional bioactivities and physicochemical properties of small-molecules are key to understand these processes. This study provides an analysis of a recently reported unique multitarget dataset for the correlation between multitarget bioactivity and physicochemistry. Six novel pan-ABC transporter inhibitors were validated containing substructural features of ABC transporter activators, which underpins the relevance of the multitarget binding site for the targeted development of novel AD diagnostics and therapeutics.

Bill Walsh Translational Cancer Research Laboratory Kolling Institute Faculty of Medicine and Health The University of Sydney St Leonards NSW 2065 Australia

Biomedical Research Centre University Hospital Hradec Kralove Sokolska 581 500 05 Hradec Kralove Czech Republic

Cancer Drug Resistance and Stem Cell Program School of Medical Science Faculty of Medicine and Health The University of Sydney Camperdown NSW 2006 Australia

Department of Pathology Section of Neuropathology Translational Neurodegeneration Research and Neuropathology Lab University of Oslo and Oslo University Hospital Sognsvannsveien 20 0372 Oslo Norway

Department of Pharmaceutical and Cellbiological Chemistry Pharmaceutical Institute University of Bonn An der Immenburg 4 53121 Bonn Germany

Department of Pharmacology Faculty of Medicine University of Latvia Jelgavas iela 4 1004 Rīga Latvia

LIED Pahnke Lab University of Lübeck and University Medical Center Schleswig Holstein Ratzeburger Allee 160 23538 Lübeck Germany

Tel Aviv University The Georg S Wise Faculty of Life Sciences Department of Neurobiology P O Box 39040 Tel Aviv 6997801 Israel

Citace poskytuje Crossref.org