Sorry to be pedantic, but I think the AurA and AurC values got mixed up. It did make me wonder, though: any idea why they might be so interested in AurC, which apart from being expressed only in testis doesn’t seem to be found anywhere else? Still got a lot to learn…
Thanks for the correction, and I think we all have a lot to learn. You likely know more then I on target selection, but I tend to thing the goal of much of this multi-targetting business is a bit like rolling the dice, and finding compounds that doesn’t kill things…
It sometimes seems that the current Angiogenesis paradigm is to have three lists of enzymes in the screening panel: Good to hit, bad to hit, and don’t know but lets see what happens.
Docking scores for CDK2 seem to suck for the macrocycles, much much better for the N-methyl analogs. Binding mode looks non-classical, with binding affinity seeming to come mainly from HBs with sulfimine and associated paraphernalia.
ic50 >> docking scores. Quit modeling and take up something useful, like crystallography k tx! [omfg so harsh]
The CDK activity is pretty easy to understand, for the general idea, check out 1OIT (AZ / BMCL). Its the Aurora activity that has me wondering what’s so special about the sulfoximine. 2NP8 suggests that it’s got something to do with ARG-137 in Aur-A.
The tether has got to be about the entropy. ‘Pre-shaping’ the molecule in a position to bind, and also for their enhanced PK.
Haha…that’s why you cannot trust docking scores blindly. Most serious modelers don’t, and certainly not for one or two compounds for a single target. I sort of just wanted to check out everyone’s reaction 😉
Thanks for the link…what do you think about the latest J. Med. Chem. p38 paper by the way?
I always thought that N,N’-diaryl ureas awere an abominatination – my last work with them ended a week ago, the two free NH and carbonyl produces the kind of stuff that gells or crystalizes from diluted ethyl acetate solutions. So I am glad that they replaced it in their BIRB series.