How many times have I heard this: “Had aspirin been discovered today, it would never have been approved”? I think that anyone who gets into reminiscing about the “good old days” knows what I am talking about. Every medicinal chemist pulls this story out and I am actually getting a bit tired of hearing it. Still, there is this undeniable scientific fact that aspirin has its share of troubles when it comes to side effects. It is also a quantifiable fact: COX-2 is aspirin’s biochemical target, but aspirin it not selective and hits COX-1 between 10 and 100-fold more efficiently. The trouble is that COX-2 is a legitimate inflammation target, whereas COX-1 is involved in gastric protection. The difference in the reactions between aspirin and these two enzymes apparently comes from the kinetics of the irreversible step. Zhang and co-workers of NYU recently published a computational study that sheds some light on the observed lack of selectivity. It was interesting to read that the fundamental difference between inhibiting the two enzymes comes from the rate difference of covalent bond formation. Aspirin is a covalent inhibitor and serves as a reminder to anyone who doubts that covalent inhibitors make good therapeutics. I am not sure that the insights one gains out of this paper are going to result in a better aspirin, but who knows – maybe there will be some bright ideas. Apparently there is something very important in the fact that His513 in COX-1 is mutated into Asp513 in COX-2. The whole topic of how covalent inhibitors work is interesting and partitioning between the non-covalent complex formation and subsequent irreversible step is especially fascinating. One of the reasons there is hope for selective covalent inhibitors is that we can learn to differentiate between enzyme targets at the first step (pre-complexation) so that attenuated electrophiles do not run amok. Aspirin is clearly not one of the good ones. But we are in 2015, so one can be optimistic about a new generation of “smarter” covalent inhibitors.