The relative frequencies of publication and substance indexing indicate that compounds containing α,β-unsaturated carbonyl compounds predominate in covalent inhibitors, occurring in roughly half of the publications discussing covalent inhibitors and making up nearly two-thirds of the compounds indexed from those articles (Figure and). The presence of US FDA-approved drugs using this set of warheads (Supplementary table ) likely reduces the risk of drug development for such compounds relative to those containing a less prevalent warhead; the reactivities of the warheads and their benefits and liabilities are better known (and may also be easier to justify to others). In addition, the acryloyl moiety is readily grafted onto amine or azaheterocyclic groups, making the development of a covalent inhibitor from a noncovalent inhibitor easier. This is reflected by the fast growth in publications for acrylamide (N derivative) warheads as compared to the modest growth of the O and C derivatives (Figure ). The difference between substance count and publications may be attributed to the presence of a significant number of approved drugs incorporating the warhead; documents comparing a novel warhead or novel substructures are likely to contain compounds with α,β-unsaturated carbonyl compounds (as well as boron compounds and epoxides) as standards. Publications discussing epoxides and aldehydes belonging to groups 3 and 2, respectively, make up the next largest fractions of warheads (after α,β unsaturated carbonyls), though their fractional contribution to the total number of warhead-containing substances is smaller than their contribution to publication count (Figure ). Both epoxides and aldehydes are also present in approved covalent inhibitors (Supplementary table ), making them less risky than less prevalent warheads; however, both epoxides and aldehydes may react with a variety of residues, including N-terminal amines and lysine, serine, threonine, and cysteine residues. While the development of covalent inhibitors reactive with amino acids such as lysine is important to find more broadly active covalent inhibitors, it also may make the reactivity of epoxide-or aldehyde-containing covalent inhibitors more difficult to predict. Among the other members of the Group 2 warheads, disulfides, boronic acids and esters and α-ketoamides exhibit comparable modest but steady growth in publications over the past two decades (Figure ). Disulfides may react reversibly with enzymes, which may provide both opportunity and uncertainty to development in covalent inhibitors. Boron compounds and α-ketoamides have been used in FDA approved covalent inhibitors (Supplementary table ) as is evidenced by an increased number of publications (Figure ). Articles pertaining to use of selenium warheads have shown a small but sharp growth in the last 3 years (Figure ). This can be partly attributed to the discovery of Ebselen's inhibition of lens-epithelium-derived growth-factor and a resurgence of interest in selenium containing small molecules. Isothiocyanates belonging to group 3 warheads, show very limited growth in publications (Figure ) while sulfonyl fluorides appear to show a faster rate of growth since 2017 (Figure ). This could be attributed to their reactivities with both lysine and cysteine residues providing sulfonyl containing covalent inhibitors with a broader scope of targets, though fewer methods likely exist for their synthesis than for chloroacetamides or acrylamides Alkyne-containing carbonyl and sulfonyl compounds and vinyl sulfonyl compounds make up significant fractions of covalent inhibitor publications and smaller contributions to the total substance count (Figure ). Like boron compounds and α-ketoamides, alkyne carbonyl compounds have also appeared in approved covalent inhibitor drugs (Supplementary table ), making them potential starting points for further development. In group 4 warheads, alkynecontaining carbonyl compounds (R-CO) have shown maximal growth in publications, followed by alkyne or alkene-containing sulfonyls (R-SO2) and nitriles (R-CN) with the nitro compounds showing the minimal/least growth (R-NO2) (Figure ). The need for multi-step synthesis of the warheads may make them more difficult to incorporate into existing noncovalent inhibitors. The increased reactivity of some warheads (alkyne carbonyl and sulfonyl compounds) or the variable selectivities of others (boron-containing inhibitors, vinyl sulfonyl compounds) may also hinder development explaining differences in their relative rates of growth.