title: Combining on-chip synthesis of a focused combinatorial library with computational target prediction reveals imidazopyridine GPCR ligands.
abstract: Using the example of the Ugi three-component reaction we report a fast and efficient microfluidic-assisted entry into the imidazopyridine scaffold, where building block prioritization was coupled to a new computational method for predicting ligand-target associations. We identified an innovative GPCR-modulating combinatorial chemotype featuring ligand-efficient adenosine A1/2B and adrenergic α1A/B receptor antagonists. Our results suggest the tight integration of microfluidics-assisted synthesis with computer-based target prediction as a viable approach to rapidly generate bioactivity-focused combinatorial compound libraries with high success rates.
authors.affiliation: Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Wolfgang-Pauli-Strasse 10, 8093 Zurich (Switzerland).
authors.forename: Michael
authors.initials: M
authors.lastname: Reutlinger
authors.forename: Tiago
authors.initials: T
authors.lastname: Rodrigues
authors.forename: Petra
authors.initials: P
authors.lastname: Schneider
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D015195:Drug Design; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D046210:Microfluidic Analytical Techniques / Q000379:methods*; D008958:Models, Molecular; D011237:Predictive Value of Tests; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D007093:Imidazoles; D008024:Ligands; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled
keywords: combinatorial chemistry; computer chemistry; drug design; microfluidics; multicomponent reactions