Lipinski in his landmark paper defined the Rule of 5 as "...poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight (MWT) is greater than 500 and the calculated log P (CLogP) is greater than 5 (or MlogP > 4.15)." (MLogP = Moriguchi Log P calculation). A compound complies with Lipinski's rule if it violates no more than one of the conditions. While once considered central to drug design for drugs intended to be orally administered, the number of drugs including those with FDA approval that violate/are exceptions to the rule of 5 has been growing. For our set of warhead containing compounds (~25 K), we calculated the number of H-bond donors, H-bond acceptors, the molecular weight and CLogP. We chose to classify our set of covalent inhibitors by how many aspects of the Rule of 5 each compound obeyed. Since most of the compounds studied are likely to be delivered orally, the use of the Rule of 5 is likely pertinent. As shown in Figure , an almost negligible fraction of substances (0.05%) followed none of Lipinski's rules while roughly 80% compounds violated none or one of the Rule of 5 conditions. About 15% and 4% of the remainder followed two or one of the rules, respectively. Thirty of 74 US FDA-approved kinase inhibitors violate Lipinski's rule of five. Of the covalent inhibitors we found, alkyne and chloro carbonyl compounds disproportionately obeyed all of the conditions of the Rule of 5, while α,β-unsaturated amides and epoxides made up a disproportionate fraction of compounds that violated one or two of the conditions of the Rule of 5. As noted by Jagannathan , roughly 60% of approved antitumor agents obeyed the molecular weight cutoff for the Rule of 5; since α,β-unsaturated carbonyl compounds such as acrylamides can be derived by addition of an acrylamide or other unsaturated acyl moiety to a known noncovalent inhibitor, the molecular weights of covalent inhibitors are likely higher than the corresponding noncovalent inhibitors and more likely to exceed the molecular weight threshold of the Rule of 5. Disulfides and selenium compounds tended to flout 3 out of 4 rules; the reason for this is unclear.