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.
Animals Cell Survival Chlorocebus aethiops Computational Chemistry Coronavirus 3C Proteaseschemistry Coronavirus Papain-Like Proteaseschemistry Crystallography, X-Ray Databases, Protein Drug Design Drug Developmentmethods Drug Discoverymethods HEK293 Cells High-Throughput Screening Assaysmethods Histone-Lysine N-Methyltransferasechemistry Humans Hydrogen Bonding Hydrophobic and Hydrophilic Interactions Ligands Protein Binding Receptors, G-Protein-Coupledchemistry SARS-CoV-2chemistrygenetics Small Molecule Libraries Vero Cells