1. Iminodiacetic Acid as a Novel Metal‐Binding Pharmacophore for New Delhi Metallo‐β‐lactamase Inhibitor Development
- Author
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Chen, Allie Y, Thomas, Caitlyn A, Thomas, Pei W, Yang, Kundi, Cheng, Zishuo, Fast, Walter, Crowder, Michael W, and Cohen, Seth M
- Subjects
Coordination Complexes ,Dose-Response Relationship ,Drug ,Humans ,Imino Acids ,Molecular Structure ,Structure-Activity Relationship ,Zinc ,beta-Lactamase Inhibitors ,beta-Lactamases ,antibiotic resistance ,aspergillomarasmine A ,iminodiacetic acid ,metal chelator ,New Delhi metallo-beta-lactamase ,New Delhi metallo-β-lactamase ,Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry - Abstract
The fungal natural product aspergillomarasmine A (AMA) has been identified as a noncompetitive inhibitor of New Delhi metallo-β-lactamase-1 (NDM-1) that inhibits by removing ZnII from the active-site. The nonselective metal-chelating properties and difficult synthesis and derivatization of AMA have hindered the development of this scaffold into a potent and selective inhibitor of NDM-1. Iminodiacetic acid (IDA) has been identified as the metal-binding pharmacophore (MBP) core of AMA that can be leveraged for inhibitor development. Herein, we report the use of IDA for fragment-based drug discovery (FBDD) of NDM-1 inhibitors. IDA (IC50 =120 μM) was developed into inhibitor 23 f (IC50 =8.6 μM, Ki =2.6 μM), which formed a ternary complex with NDM-1, as evidenced by protein thermal-shift and native-state electrospray ionization mass spectrometry (ESI-MS) experiments. Combining mechanistic analysis with inhibitor derivatization, the use of IDA as an alternative AMA scaffold for NDM-1 inhibitor development is detailed.
- Published
- 2020