Fragment-based drug discovery (FBDD) is a powerful tool that has led to the recent approval of several small molecule drugs. While traditional fragment libraries typically achieve high chemical diversity, their topological coverage is often limited due to the mostly linear or flat composition of many fragment molecules. To address this shortcoming, we present a library of “metallofragments” that is composed of both inert and reactive metal complexes that can achieve high shape diversity. These metal complexes provide easy access to highly three-dimensional structures that are not readily attained using solely organic molecules. The three-dimensionality of these metallofragments is quantified using principal moment of inertia analysis, and the topological diversity of these molecules is demonstrated by comparison to molecules associated with typical fragment libraries. Inert metallofragments may bind to the active site of a particular target through hydrogen bonding and van der Waals interactions, while reactive fragments are uniquely suited form strong covalent coordinate bonds between surface amino acid residues and the metal center. These metallofragments were evaluated against several targets with relevance to disease indications including viral, bacterial, and cancer targets. Good inhibition of these targets was observed, indicating that metallofragments may serve as promising starting points in FBDD campaigns.

Metallofragments as 3D scaffolds for fragment-based drug discovery

ACS Spring 2022

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