Structure-based virtual screening discovers potent and selective adenosine A1 receptor antagonists

• Published in: European journal of medicinal chemistry 2023-09, Vol.257, p.115419-115419, Article 115419
• Main Authors: Matricon, Pierre, Nguyen, Anh TN, Vo, Duc Duy, Baltos, Jo-Anne, Jaiteh, Mariama, Luttens, Andreas, Kampen, Stefanie, Christopoulos, Arthur, Kihlberg, Jan, May, Lauren Therese, Carlsson, Jens
• Format: Article
• Language: English
• Subjects: Computer-aided drug design; G protein-coupled receptor; Molecular docking; Selectivity
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115419

Development of subtype-selective leads is essential in drug discovery campaigns targeting G protein-coupled receptors (GPCRs). Herein, a structure-based virtual screening approach to rationally design subtype-selective ligands was applied to the A1 and A2A adenosine receptors (A1R and A2AR). Crystal structures of these closely related subtypes revealed a non-conserved subpocket in the binding sites that could be exploited to identify A1R selective ligands. A library of 4.6 million compounds was screened computationally against both receptors using molecular docking and 20 A1R selective ligands were predicted. Of these, seven antagonized the A1R with micromolar activities and several compounds displayed slight selectivity for this subtype. Twenty-seven analogs of two discovered scaffolds were designed, resulting in antagonists with nanomolar potency and up to 76-fold A1R-selectivity. Our results show the potential of structure-based virtual screening to guide discovery and optimization of subtype-selective ligands, which could facilitate the development of safer drugs. [Display omitted] •Virtual screening for subtype-selective adenosine A1 receptor ligands was performed.•4.6 million compounds were docked to A1 and A2A adenosine receptor crystal structures.•Seven of the 20 predicted ligands were experimentally confirmed as A1 antagonists.•Structure-guided optimization identified potent and subtype-selective A1 antagonists.