Using Coordination Chemistry to Get Out of ‘Flat Land’
13The use of metal complexes to augment or modify existing organic drug-like molecules has been studied for decades. Among the more contemporary and successful efforts in this space has been the use of kinetically and thermodynamically inert metal centers to modify staurosporine, a known kinase inhibitor. These bioinorganic derivatives of staurosporine successfully produced a wide range of selective and potent kinase inhibitors by exploiting the rich 3-dimensional (3D) shapes afforded by these metal centers and their spectator ligands. In these derivatives, the metal centers effectively act as isosteres (or bioisosteres) for a cyclic carbohydrate found in native staurosporine. Inspired by this work and others’, this presentation will focus on the use of small, stable coordination compounds to act as core 3D scaffolds for fragment-based drug discovery (FBDD). Rather than modifying known bioactive molecules, coordination compounds are used as the basis for inhibitor discovery. FBDD may suffer from a lack of 3D organic fragments that coordination compounds can readily provide. The Cohen Lab’s successes and challenges in implementing this strategy, with a focus on coordinate covalent inhibitors of proteases (e.g., the SARS-CoV-2 main protease), will be discussed.
Speaker: Prof. Dr. Seth Cohen (University of California, San Diego)
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