Miranda-Pastoriza Darío, Bernárdez Rodrigo, Azuaje Jhonny, Prieto-Díaz Rubén, Majellaro Maria, Tamhankar Ashish V, Koenekoop Lucien, González Alejandro, Gioé-Gallo Claudia, Mallo-Abreu Ana, Brea José, Loza M Isabel, García-Rey Aitor, García-Mera Xerardo, Gutiérrez-de-Terán Hugo, Sotelo Eddy
Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS) and Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Department of Cell and Molecular Biology, SciLifeLab, Uppsala University, Uppsala SE-75124, Sweden.
ACS Med Chem Lett. 2022 Jan 10;13(2):243-249. doi: 10.1021/acsmedchemlett.1c00598. eCollection 2022 Feb 10.
A library of potent and highly AAR selective pyrimidine-based compounds was designed to explore non-orthosteric interactions within this receptor. Starting from a prototypical orthosteric AAR antagonist (ISVY130), the structure-based design explored functionalized residues at the exocyclic amide L1 region and aimed to provide additional interactions outside the AAR orthosteric site. The novel ligands were assembled through an efficient and succinct synthetic approach, resulting in compounds that retain the AAR potent and selective profile while improving the solubility of the original scaffold. The experimentally demonstrated tolerability of the L1 region to structural functionalization was further assessed by molecular dynamics simulations, giving hints of the non-orthosteric interactions explored by these series. The results pave the way to explore newly functionalized AAR ligands, including covalent drugs and molecular probes for diagnostic and delivery purposes.
设计了一个包含强效且高度AAR选择性嘧啶类化合物的文库，以探索该受体内部的非正构相互作用。从典型的正构AAR拮抗剂（ISVY130）出发，基于结构的设计探索了环外酰胺L1区域的官能化残基，旨在在AAR正构位点之外提供额外的相互作用。通过高效简洁的合成方法组装了新型配体，得到的化合物保留了AAR的强效和选择性特征，同时提高了原始支架的溶解度。通过分子动力学模拟进一步评估了实验证明的L1区域对结构官能化的耐受性，为这些系列所探索的非正构相互作用提供了线索。这些结果为探索新的官能有化AAR配体铺平了道路，包括用于诊断和递送目的的共价药物和分子探针。
