ABSTRACT
Fragment-based drug design has introduced a bottom-up process for drug development, with improved sampling of chemical space and increased effectiveness in early drug discovery. Here, we combine the use of pharmacophores, the most general concept of representing drug-target interactions with the theory of protein hotspots, to develop a design protocol for fragment libraries. The SpotXplorer approach compiles small fragment libraries that maximize the coverage of experimentally confirmed binding pharmacophores at the most preferred hotspots. The efficiency of this approach is demonstrated with a pilot library of 96 fragment-sized compounds (SpotXplorer0) that is validated on popular target classes and emerging drug targets. Biochemical screening against a set of GPCRs and proteases retrieves compounds containing an average of 70% of known pharmacophores for these targets. More importantly, SpotXplorer0 screening identifies confirmed hits against recently established challenging targets such as the histone methyltransferase SETD2, the main protease (3CLPro) and the NSP3 macrodomain of SARS-CoV-2.
Subject(s)
Coronavirus 3C Proteases/chemistry , Coronavirus Papain-Like Proteases/chemistry , Drug Development/methods , Drug Discovery/methods , High-Throughput Screening Assays/methods , Histone-Lysine N-Methyltransferase/chemistry , Animals , Cell Survival , Chlorocebus aethiops , Computational Chemistry , Crystallography, X-Ray , Databases, Protein , Drug Design , HEK293 Cells , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Ligands , Protein Binding , Receptors, G-Protein-Coupled/chemistry , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Small Molecule Libraries , Vero CellsABSTRACT
An efficient and convenient solution-phase synthesis of a 1H-1,2,4-triazole library with potential agrochemical activity is reported employing microwave-assisted organic synthesis (MAOS) and continuous-flow microfluidic synthetic methods starting from commercially available 3,5-dibromo-1H-1,2,4-triazole (1). MAOS was used for the synthesis of 5-amino-3-bromo-1,2,4-triazole analogs 3 and for their 3-aryl derivatives 4 via Suzuki-Miyaura coupling with polymer-supported catalyst. A microfluidic hydrogenation reactor integrated into an automated parallel synthesis platform was built and utilized for the reductive dehalogenation reactions providing 5-aminotriazoles (5).
Subject(s)
Combinatorial Chemistry Techniques/methods , Microfluidics/methods , Microwaves , Rheology , Triazoles/chemistry , Triazoles/chemical synthesis , Amines/chemistry , Bromides/chemistry , Magnetic Resonance Spectroscopy , Molecular Weight , Solvents/chemistryABSTRACT
We describe here an efficient and versatile method for the preparation of 3-imidazo[1,2-a]pyridin-3-yl-propionic acids involving, as a key step, a three-component Michael-type reaction. The extended and validated procedure allowed us to prepare various acids with three diversity points. The method was easily adaptable for parallel synthesis and an approximately 2000-membered 3-imidazo[1,2-a]pyridin-3-yl-propionic acid amide library was prepared in a semiautomated manner.