Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics

Vigneshwaran Namasivayam; Katja Stefan; Jens Pahnke; Sven Marcel Stefan

doi:10.1016/j.csbj.2021.11.035

Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics

Comput Struct Biotechnol J. 2021 Nov 27:19:6490-6504. doi: 10.1016/j.csbj.2021.11.035. eCollection 2021.

Authors

Vigneshwaran Namasivayam¹, Katja Stefan², Jens Pahnke^{2

3

4}, Sven Marcel Stefan²

Affiliations

¹ Department of Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
² Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab (www.pahnkelab.eu), University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway.
³ LIED, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
⁴ Department of Pharmacology, Faculty of Medicine, University of Latvia, Jelgavas iela 1, 1004 Rīga, Latvia.

Abstract

The adenosine-triphosphate-(ATP)-binding cassette (ABC) transporter ABCA7 is a genetic risk factor for Alzheimer's disease (AD). Defective ABCA7 promotes AD development and/or progression. Unfortunately, ABCA7 belongs to the group of 'under-studied' ABC transporters that cannot be addressed by small-molecules. However, such small-molecules would allow for the exploration of ABCA7 as pharmacological target for the development of new AD diagnostics and therapeutics. Pan-ABC transporter modulators inherit the potential to explore under-studied ABC transporters as novel pharmacological targets by potentially binding to the proposed 'multitarget binding site'. Using the recently reported cryogenic-electron microscopy (cryo-EM) structures of ABCA1 and ABCA4, a homology model of ABCA7 has been generated. A set of novel, diverse, and potent pan-ABC transporter inhibitors has been docked to this ABCA7 homology model for the discovery of the multitarget binding site. Subsequently, application of pharmacophore modelling identified the essential pharmacophore features of these compounds that may support the rational drug design of innovative diagnostics and therapeutics against AD.

Keywords: ABC transporter (ABCA1, ABCA4, ABCA7); ABC, ATP-binding cassette; AD, Alzheimer’s disease; APP, amyloid precursor protein; ATP, Adenosine-triphosphate; Alzheimer’s disease (AD); BBB, blood-brain barrier; BODIPY-cholesterol, 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene-cholesterol; ECD, extracellular domain; EH, extracellular helix; GSH, reduced glutathione; HTS, high-throughput screening; IC, intracellular helix; MOE, Molecular Operating Environment; MSD, membrane spanning domain; Multitarget modulation (PANABC); NBD, nucleotide binding domain; NBD-cholesterol, 7-nitro-2-1,3-benzoxadiazol-4-yl-cholesterol; PDB, protein data bank; PET tracer (PETABC); PET, positron emission tomography; PLIF, protein ligand interaction; PSO, particle swarm optimization; Polypharmacology; R-domain/region, regulatory domain/region; RMSD, root mean square distance; Rational drug design and development; SNP, single-nucleotide polymorphism; TM, transmembrane helix; cryo-EM, cryogenic-electron microscopy.