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 cryo-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.

三磷酸腺苷 (ATP) 结合盒 (ABC) 转运蛋白 ABCA7 是阿尔茨海默病 (AD) 的遗传风险因素。有缺陷的 ABCA7 会促进 AD 的发展和/或进展。不幸的是，ABCA7 属于小分子无法解决的“研究不足”的 ABC 转运蛋白组。然而，这种小分子将允许探索 ABCA7 作为开发新 AD 诊断和治疗方法的药理学靶点。泛 ABC 转运蛋白调节剂通过潜在地与提议的“多靶点结合位点”结合，继承了探索研究不足的 ABC 转运蛋白作为新药理学靶点的潜力。使用最近报道的 ABCA1 和 ABCA4 的冷冻电子显微镜 (cryo-EM) 结构，已经生成了 ABCA7 的同源模型。一套新颖、多样、有效的泛 ABC 转运蛋白抑制剂已与该 ABCA7 同源模型对接，以发现多靶点结合位点。随后，药效团建模的应用确定了这些化合物的基本药效团特征，这些特征可能支持针对 AD 的创新诊断和治疗的合理药物设计。