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

• Published in: Computational and structural biotechnology journal Vol. 19; pp. 6490 - 6504
• Main Authors: Namasivayam, Vigneshwaran, Stefan, Katja, Pahnke, Jens, Stefan, Sven Marcel
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2021; Research Network of Computational and Structural Biotechnology; Elsevier
• Subjects: ABC transporter (ABCA1, ABCA4, ABCA7); Alzheimer’s disease (AD); Multitarget modulation (PANABC); PET tracer (PETABC); Polypharmacology; Rational drug design and development; APP; ABC; BBB; HTS; Polypharmacology; PDB; NBD; ABC transporter (ABCA1, ABCA4, ABCA7); Multitarget modulation (PANABC); Alzheimer’s disease (AD); SNP; BODIPY-cholesterol; IC; cryo-EM; GSH; MSD; MOE; AD; EH; ECD; R-domain/region; RMSD; PSO; Rational drug design and development; NBD-cholesterol; TM; PLIF; PET tracer (PETABC); ATP; PET; GSH, reduced glutathione; cryo-EM, cryogenic-electron microscopy; PLIF, protein ligand interaction; AD, Alzheimer’s disease; SNP, single-nucleotide polymorphism; BBB, blood-brain barrier; ABC, ATP-binding cassette; MOE, Molecular Operating Environment; R-domain/region, regulatory domain/region; TM, transmembrane helix; MSD, membrane spanning domain; PET, positron emission tomography; HTS, high-throughput screening; IC, intracellular helix; BODIPY-cholesterol, 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene-cholesterol; ECD, extracellular domain; NBD-cholesterol, 7-nitro-2-1,3-benzoxadiazol-4-yl-cholesterol; ATP, Adenosine-triphosphate; NBD, nucleotide binding domain; PDB, protein data bank; PSO, particle swarm optimization; EH, extracellular helix; RMSD, root mean square distance; APP, amyloid precursor protein
• ISSN: 2001-0370; 2001-0370
• DOI: 10.1016/j.csbj.2021.11.035

[Display omitted] 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.