On-DNA Platform Molecules Based on a Diazide Scaffold II: A Compact Diazide Platform Designed for Small-Molecule Drug Discovery.

Expanding the chemical diversity of DNA-encoded libraries (DELs) is crucial for identifying binders to emerging drug targets using DEL technology. In the present study, as part of our ongoing efforts to develop on-DNA diazide platforms (D-DAPs)-platform molecules possessing both aromatic and aliphatic azide groups on a single core reactive scaffold-we designed and synthesized a new compact diazide platform, designated as a compact D-DAP (C-D-DAP). This molecule is based on a low-molecular-weight reactive scaffold, 3-azido-5-(azidomethyl)benzoic acid, to facilitate small-molecule drug discovery targeting enzymes and G protein-coupled receptors (GPCRs). Furthermore, we established two distinct stepwise warhead construction strategies that exploit the chemoselective transformations of the azide groups in the C-D-DAP, which exhibit different reactivities. In addition, four virtual DELs were generated based on stepwise warhead elaboration from the C-D-DAP scaffold. Comparative chemical diversity analysis against bioactive compounds from ChEMBL revealed that these virtual libraries populate structural regions that are sparsely represented among known molecules. Each virtual library also occupies a distinct region of structural space relative to the others and displays intermediate quantitative estimate of drug-likeness (QED) values.