Click chemistry for natural product-inspired covalent drug discovery

Metabolites, including primary and secondary metabolites, the latter often termed 'natural products' (NPs), offer a structurally rich source of scaffolds for drug discovery. Although many act through reversible binding, a notable subset exerts potent effects via covalent mechanisms, offering distinct advantages. Advances in click chemistry now enable modular incorporation of electrophilic warheads and bioorthogonal handles onto NP frameworks, facilitating the discovery of new covalent agents and the mapping of their biological activity. In this review, we highlight key classes of 'click electrophiles' and their integration into NP scaffolds, examine how click chemistry supports activity-based protein profiling (ABPP) of covalent NPs, and introduce clickable covalent metabolite mimetics (CoMMs) as a unifying framework for advancing inverse covalent drug discovery.