Reactivity of Covalent Fragments and Their Role in Fragment Based Drug Discovery

Abstract

Fragment based drug discovery has long been used for the identification of new ligands and interest in targeted covalent inhibitors has continued to grow in recent years, with high profile drugs such as osimertinib and sotorasib gaining FDA approval. It is therefore unsurprising that covalent fragment-based approaches have become popular and have recently led to the identification of novel targets and binding sites, as well as ligands for targets previously thought to be 'undruggable'. Understanding the properties of such covalent fragments is important, and characterizing and/or predicting reactivity can be highly useful. This review aims to discuss the requirements for an electrophilic fragment library and the importance of differing warhead reactivity. Successful case studies from the world of drug discovery are then be examined.

Keywords: covalent fragments; electrophilic warhead; fragment library; fragment-based drug discovery; reactivity.

Figure 1

Representative examples of FDA approved covalent inhibitors Osimertinib (2015), afatinib (2013), acalabrutinib (2017), and sotorasib (2021) alongside their targeted proteins. Reactive groups are highlighted in blue [2,9,10].

Figure 2

Representative warhead motifs and overlap of amino acid activity. Colours represent selected amino acids which have been labelled in the literature by those warheads; yellow—cysteine, blue—lysine, red—serine/threonine. Where overlap occurs the corresponding secondary colour is observed [14,36].

Figure 3

KRAS_G12C covalent inhibitors.

Figure 4

(a) Covalent fragment binders of Sars-Cov2 main protease; (b) Reaction scheme of covalent modification to Cys145 by 3-bromoprop-2-yn-1-yl amides.

Figure 5

Small molecule binders of BRD4.

Figure 6

(a) Structure of sulfopin; (b) Structures of GPX4 covalent binders.

Figure 7

Fragment merging and elaboration of LP-Pla2 small molecule inhibitors.