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.
Highlights
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
Experimental fragment pharmacophores were extracted from the available protein-fragment structures in the Protein Data Bank
Regions that bind multiple probe clusters are defined as the predicted binding hotspots. (The method is described in more detail in the Supplementary Information, section 1.3.) Schrödinger’s ePharmacophore module was employed to extract a pharmacophore model for each protein–ligand complex
Summary
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. Using this information, we design a minimal diverse set of commercial fragments (the SpotXplorer[0] library) covering the majority of the experimental binding pharmacophores to be used for the identification of fragment starting points for drug discovery targets. We design a minimal diverse set of commercial fragments (the SpotXplorer[0] library) covering the majority of the experimental binding pharmacophores to be used for the identification of fragment starting points for drug discovery targets After validating this library against established target classes and reproducing a majority of the known binding pharmacophores, we address more challenging targets. We present promising starting points for two recent COVID-19 targets, the 3CL main protease and the NSP3 macrodomain of SARS-CoV-2
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