A New Perspective in Chemical Probe Discovery: Expanding Virtual Screening into Metal Complex Chemical Space

Transition metal complexes provide rigid, shape-defined molecular architectures in which the coordination geometry precisely organizes ligand functionality in three dimensions, making them attractive scaffolds for target-based chemical probe discovery. Yet, their broader and prospective use in structure-based virtual screening has remained largely unexplored, due to the absence of structurally diverse, computationally tractable screening libraries. Here, we address this by curating MOSAIC (Metal complex library for Structure-Aided In silico screening), a first collection of 16,901 neutral, drug-like metal complexes assembled directly from experimentally determined geometries deposited in the Cambridge Structural Database. Using MOSAIC , we perform a high-throughput virtual screening campaign against the allosteric pocket of methionine adenosyltransferase 2A (MAT2A), identifying the copper complex Cu1-Complex , for which nano differential scanning fluorimetry (nanoDSF) confirmed strong binding in vitro . The diamagnetic zinc analogue Zn1-Comple x allowed orthogonal binding characterization with ligand-observed and competition NMR studies. Along with Hydrogen–deuterium exchange mass spectrometry (HDX-MS), site-directed mutagenesis and molecular dynamics (MD), these studies show that Zn1-Complex engages the MAT2A through an allosteric pocket, inhibiting enzymatic activity. Together, this establishes MOSAIC as a scalable and generalizable virtual screening platform for transition metal complexes and demonstrates the potential of these metal-based scaffolds as chemical probes to uncover new modes of protein recognition.