The researchers performed a functional screen of a small fragment library. Among many hits, the most potent were compounds 1 and 2, both with high ligand efficiencies. When these were linked together the resulting compound 3 had an improved potency, and adding a small substituent to yield compound 4 gave a sub-micromolar inhibitor.
Remarkably, not only was compound 4 potent against falcipain-1, it was also potent against several other important disease targets. In recognition of this pan-potency, the researchers have named compound 4 “hitinane.” Whether or not this discovery will lead to a drug, it undoubtedly will fuel many papers, patents, and grant proposals.
Surely this should be in Chemistry & Biology?
ReplyDeletePerhaps less lighthearted than previous April Fools’ posts, this one reflects my continuing frustration with some of the (to put it politely) “refuse” published in the literature. Compound 1 is a known hydrogen-peroxide generator (which would inactivate cysteine proteases) and compound 2 is an electrophilic rhodanine (which Jonathan Baell has memorably referred to as “polluting the literature”). I added the catechol (which can form reactive ortho-quinones) in compound 4 just to push things completely over the top.
ReplyDeleteIf any of these molecules don’t make you cringe, please review the literature on PAINS before submitting your next paper for publication. And no matter what your molecules look like, please don’t forget to add detergent to your assay!
Would love to see a reference for the H2O2 generating fragment. Any other small molecules do the same thing? I learned something new today! Woot!
ReplyDeleteYes, these redox compounds are particularly insidious. One of the first references is here. There is an excellent paper discussing their presence in the NIH small molecule repository here and a good review here.
ReplyDeleteSweet, Much as the ancient Alchemists searched for a universal solvent, it seems the modern alchemists search for a universal inhibitor...
ReplyDelete