The primary objective of this proposal is to identify stable and structurally diverse metal complexes that can serve as 3-dimensional fragments for fragment-based drug discovery (FBDD). FBDD is a powerful drug discovery strategy, but is limited by fragments that are only organic molecules, which results in predominantly 1-dimensional and 2-dimensional molecular shapes. This restricts the topological chemical space that is readily explored by FBDD. We propose to develop methods to identify, optimize, and utilize stable transition metal complexes, so-called metallofragments, to fill this void in 3-dimensional fragment space for FBDD. To establish metallofragments as a viable solution to this problem, this proposal seeks to complete two specific aims.
In Specific Aim 1, metallofragments will be designed and synthesized to produce a fragment library with rich 3-dimensional shape diversity. To ensure biochemical stability, the pharmacokinetic properties of metallofragments will be tested using several stability assays (e.g. plasma and microsomal stability).
In Specific Aim 2, the metallofragment library will be screened against influenza endonuclease using X-ray crystallography, enzymatic FRET assays, and thermal shift analysis. Hits will be modified to improve binding affinity and selectivity against endonuclease. Endonuclease will serve to demonstrate the potential of the metallofragment library. Data collected in the laboratory of the PI suggests that the endonuclease active site will be highly amenable to targeting by 3-dimensional metallofragments. This project will test the central hypothesis of whether metal-based fragments can fill a critical gap in the chemical space explored by FBDD. In the long term, therapeutics derived from metallofragments will demonstrate attractive features that will be enabled by the studies performed here. For example, lead molecules could be transformed into ?theranostics? simply by changing the choice of metal in (e.g. 99Tc). Similarly, non-covalent inhibitors could be converted into covalent inhibitors, by utilizing slightly more reactive metal centers. Hence, in addition to exploring 3-dimensional fragment space, this proposal will set the groundwork for exploiting several advantages afforded by metallofragment-derived therapeutics.

Public Health Relevance

Fragment-based drug discovery (FDBB) is an important strategy for developing new therapeutics, but is presently limited by a dearth of 3-dimensional chemical scaffolds. This project seeks to develop `metallofragments' to augment the exploration of 3-dimensional fragment space for FBDD. The demonstration that stable metal complexes can act as 3-dimensional scaffolds for drug discovery will fill a vital knowledge gap in the design and development of inhibitors against challenging, but valuable therapeutic targets.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Krafft, Amy
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University of California, San Diego
Schools of Arts and Sciences
La Jolla
United States
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