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

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.

Graphical abstract

Fig. 1

The only known small-molecule modulators of ABCA7.

Fig. 2

Drugs and drug-like compounds that were discovered as truly multitarget pan-ABC transporter inhibitors.

Fig. 3

Selection of focused pan-ABC transporter inhibitors used in the present study.

Fig. 4

Structural information and conformational representation of ABCA transporters that can be found in the literature , , using Molecular Operating Environment (MOE) version 2019.01 . (A) Cryo-EM structure of human ABCA1 as reported by Qian et al. in 2017 . (B) Cryo-EM structure of human ABCA4 as reported by Xie et al. in 2021 . (C) Cryo-EM structure of human ABCA4 as reported by Liu et al. in 2021 . (D) Cryo-EM structure of human ABCA4 as reported by Scortecci et al. in 2021 (E) Homology model of human ABCA7 generated from the cryo-EM structure of human ABCA1 . The membrane bilayers in (A)–(E) are indicated as brown balls and light brown areas. (F) simplified scheme of the organization of ABCA7 and its structural components. The inter-membrane space is indicated as light brown area, and the border to the cytosol and lumen is indicated by brown lines.

Fig. 5

Blind docking using the herein described homology model of ABCA7 applying AutoDock . (A) Space chosen for the blind docking experiments within the membrane bilayer indicated with brown balls and a light brown area. (B) Superimposed top ranking docking poses of the ten chosen pan-ABC transporter inhibitors 9–11, 14, 17, and 22–26, , , , , , amongst the 50 docking poses generated by AutoDock (colored cyan, stick representation) within the MSDs of the ABCA7 homology model. (C) Close-up of the superimposed top ranking poses of the docked molecules 9–11, 14, 17, and 22–26, , , , , , . Nonpolar hydrogen atoms were omitted, and polar hydrogen, carbon, nitrogen, oxygen, as well as sulfur atoms were colored in silver white, cyan, blue, red, and dark yellow, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 6

Pharmacophore model using the top ranking docking poses of compounds 9–11, 14, 17, and 22–26, , , , , , obtained from AutoDock . (A) Superimposed top ranking poses of the docked compounds 9–11, 14, 17, and 22–26, , , , , , from which the four pharmacophore features F1–F4 could be deduced (colored cyan, stick representation). Nonpolar hydrogen atoms were omitted, and polar hydrogen, carbon, nitrogen, oxygen, as well as sulfur atoms were colored in silver white, cyan, blue, red, and dark yellow, respectively. (B) The four pharmacophore features F1–F2 (aromatic/hydrophobic), F3 (aromatic), and F4 (acceptor/donor) are depicted in orange (F1–F3) as well as silver (F4). The distances between the individual features are indicated as light green lines and are outlined in the table. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 7

Blind docking using the herein described homology model of ABCA7 applying Glide , . (A) Superimposed top ranking docking poses of the pan-ABC transporter inhibitors 9–11, 14, 17, and 22–26, , , , , , amongst the 10 docking poses generated by Glide , (colored yellow, stick representation) within the MSDs of the ABCA7 homology model. (B) Close-up of the superimposed top ranking poses of the docked molecules 9–11, 14, 17, and 22–26, , , , , , . Nonpolar hydrogen atoms were omitted, and polar hydrogen, carbon, nitrogen, oxygen, as well as sulfur atoms were colored in silver white, yellow, red, blue, and dark yellow, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 8

Extended docking experiments with compounds 6–8, 12–13, 15–16, 18–21, and 27–28, , , , , , , for model validation purposes. (A) Superimposed top ranking docking poses of the compounds obtained from AutoDock . (B) Close-up of the superimposed top ranking poses of the docked molecules. (C) Superimposed top ranking docking poses of the compounds obtained from Glide , . (D) Close-up of the superimposed top ranking poses of the docked molecules. The compounds are colored in cyan (A)–(B) as well as yellow (C)–(D) and are shown in stick representation. Nonpolar hydrogen atoms were omitted, and polar hydrogen, carbon, nitrogen, oxygen, as well as sulfur atoms were colored in silver white, cyan/yellow, blue, red, and dark yellow, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 9

2D interaction diagram of the top ranking docking poses of compound 15 and possible strong interactions with amino acids of the multitarget binding site generated by PLIF implemented in MOE 2019.01 . (A) Possible interactions obtained from AutoDock formed with phenylalanine 1544 and cysteine 1653. (B) Possible interactions obtained from Glide , formed with leucine 662 and cysteine 1653. Hydrophobic and polar amino acids are shown in green circles and purple circles, respectively. Interactions with the amino acids are depicted as green dotted arrows (side chain acceptor) or green dotted lines (aromatic). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 10

Distribution of the 23 docked compounds that may form possible interactions with amino acids in the MSDs of the generated homology model of ABCA7. (A) Bar code diagram and (B) population of the 23 docked compounds as obtained from AutoDock [129]). (C) Bar code diagram and (D) population of the 23 docked compounds as obtained from Glide , . Single or multiple interactions are indicated with single and multiple columns, respectively. The respective engaged compound is indicated in the bar code diagram.