Did you know that more than 30% of therapeutic agents exert their mode of action by some sort of covalent mechanism? I find this number quite impressive, considering the continuing fear of covalence in the pharmaceutical industry. What is most interesting is that the number quoted includes molecules that were developed to act as covalent inhibitors as well as those (the vast majority) whose mechanism of action was only later determined to be covalent.
My lab has interest in covalent inhibitors and I included this subject in one of my recent 4th year chemistry classes. I realized today that there was one paper I forgot to mention. It is a good one because avibactam’s mechanism of action is unique: the strained urea engages beta-lactamase covalently and is subsequently “resurrected” to its original form. Incidentally, I am not making any strong hints to the origin of the 70% “truly” non-covalent drugs mentioned earlier and I do not want you to think that there are even more covalent inhibitors out there, but you never know.
a more common example of reversibly covalent binding is addition of peptide-aldehydes and peptide-ketoamides to SH bonds in protease active sites.
Do you have a citation for that 30% number? I couldn’t find it in the paper that you link to. Thanks!
By all means: http://www.sciencedirect.com/science/article/pii/S0960894X13011876.
This is true, there are many of those… But I am not sure how many are approved therapeutics.