A Systematic Scaffold-Centric Atlas of Amide Chemical Space: Enabling Intentional Polypharmacology and Regiochemical-Aware Scaffold Hopping

Amide functionalities are the most ubiquitous motifs in medicinal chemistry, yet their structural organization and translational significance remain largely unexplored at the scaffold level. Here, we present a comprehensive, scaffold-centric mapping of amide-containing chemical space derived from high-confidence ChEMBL bioactivity data. Crucially, we introduce the unified C(=O)N scaffold definition, a computational strategy that consolidates substitution-site variability and preserves exit vectors to overcome the structural "noise" of traditional scaffold decomposition. From a dataset of nearly 2,900,000 compounds, we distilled 17,769 chemically distinct unified C(=O)N scaffolds, 3991 of which were identified within high-confidence bioactive molecules. Structural characterization reveals that these scaffolds are predominantly compact, ring-based cores with balanced aromaticity and moderate three-dimensionality. Target profiling identified strong enrichment in kinases, epigenetic regulators, and proteases, with a subset of prevalent motifs exhibiting pronounced cross-family promiscuity. By systematically mapping the interfamily target landscape, we identified shared amide-based templates enabling "scaffold-merging" strategies for dual-target compound design (e.g., VEGFR2-PARP1), offering a chemically efficient alternative to traditional pharmacophore-linking. The practical utility of this atlas is demonstrated through a scaffold hopping case study for a BTK inhibitor, identifying structurally diverse noncovalent candidates that retain essential binding geometries. Furthermore, 15 year temporal analyses confirm the sustained evolutionary growth of these scaffolds in the global pharmacopeia. Taken together, this work provides a quantitative analysis for rational scaffold prioritization and bioisosteric hopping, underscoring the structural versatility and utility of C(=O)N scaffolds in drug discovery.