Expanding metal complex enzyme inhibitor discovery through high-throughput virtual screening
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Mika Kintzel Yew Mun Yip Daniella Hares Jonathan Bailey Alain Oregioni Sarah Maslen Simone Kunzelmann Kesavan Babu Lygia Silva de Moraes Luiz Pedro Carvalho Marcus Fischer Mark Skehel Geoff Kelly Joanna Redmond Jeannine HessThis article is a preprint. Preprints have not been peer-reviewed.
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Abstract
Transition metal complexes occupy regions of three- dimensional chemical space that organic scaffolds cannot easily reach, yet their use in target-based drug discovery has been held back by the absence of structurally diverse, readily available screening libraries. We addressed 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. Docking this library against the allosteric site of the oncology target MAT2A (methionine adenosyltransferase 2A) with MetalDock returned the copper complex Cu1-Complex, from which we designed the diamagnetic zinc analogue Zn1-Complex for detailed study. A combination of nanoDSF, ligandobserved and competition NMR, HDX-MS, site-directed mutagenesis and molecular dynamics placed Zn1-Complex in the allosteric pocket and showed that it engages the site differently from the established inhibitor Pf-9366, while functionally inhibiting the enzyme. Together, these results establish MOSAIC as a validated, generalisable platform for target-based metal complex discovery as the first scalable strategy for systematically exploiting metal complexes against any well-defined binding site.
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chemRxiv
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