Exploring Non-orthosteric Interactions with a Series of Potent and Selective A(3) Antagonists

Autor: Darío Miranda-Pastoriza, Rodrigo Bernárdez, Jhonny Azuaje, Rubén Prieto-Díaz, Maria Majellaro, Ashish V. Tamhankar, Lucien Koenekoop, Alejandro González, Claudia Gioé-Gallo, Ana Mallo-Abreu, José Brea, M. Isabel Loza, Aitor García-Rey, Xerardo García-Mera, Hugo Gutiérrez-de-Terán, Eddy Sotelo
Přispěvatelé: Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares, Universidade de Santiago de Compostela. Departamento de Química Orgánica
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
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Popis: A library of potent and highly A3AR selective pyrimidine-based compounds was designed to explore non-orthosteric interactions within this receptor. Starting from a prototypical orthosteric A3AR antagonist (ISVY130), the structure-based design explored functionalized residues at the exocyclic amide L1 region and aimed to provide additional interactions outside the A3AR orthosteric site. The novel ligands were assembled through an efficient and succinct synthetic approach, resulting in compounds that retain the A3AR 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 A3AR ligands, including covalent drugs and molecular probes for diagnostic and delivery purposes This work has received financial support from the Consellería de Cultura, Educación e Ordenación Universitaria [Galician Government (grant: ED431B 2020/43)], the Xunta de Galicia (Centro singular de investigación de Galicia accreditation 2019-2022, ED431G 2019/03), the European Union (European Regional Development Fund - ERDF), the Swedish Research Council (grant: 521-2014-2118), and the Swedish strategic research program eSSENCE. The computational studies were conducted with the resources available from the Swedish National Infrastructure for Computing (SNIC). The project was carried out within the framework of the collaborative EU COST action ERNEST (CA18133) SI
Databáze: OpenAIRE
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