Fragment-based drug discovery (FBDD) has emerged as a powerful and efficient way to develop small molecule inhibitors. Though fragment libraries are typically small in size, they are able to concisely represent broad chemical diversity. However, one shortcoming associated with this approach is that most fragment libraries are biased toward small, flat molecules. Accordingly, there has been a recent concerted effort to improve the three-dimensionality of fragment libraries. In an attempt to improve the structural diversity of common fragment libraries, our lab has developed an innovative library designed to consist of more three-dimensional fragments than are typically employed in FBDD. By using small, inert metal complexes, we have developed a novel library of “metallofragments.” This modest library is highly three-dimensional, as demonstrated by a principle moment of inertia plot. To demonstrate the capacity of the metallofragment library it was screened against influenza endonuclease. Several classes of metallofragments were identified as hits. The structure-activity relationship around the metallofragment binding site is being explored in order to identify an elaborated, full-length inhibitor molecule.

3-Dimensional metal complexes as scaffolds for fragment-based drug discovery

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.