Field of Science

Water-inhibitor synergy in CDKs

An interesting paper published in the J. Chem. Inf. Mod. investigates the role of water molecules in CDK2 and CDK5 active sites. The authors use MD simulations to simulate water and inhibitors (in this case the well-known indirubin analogs) in the active site of the CDKs. The interesting observation they make is that in some cases, the inhibitor "recruits" a water molecule to form a bridged interaction with an atom in the protein, thus achieving the "correct" binding mode. In other cases, blockage of the active site by a loop prevents this water grabbing trick.

The study also highlights how it can make a big difference between using monomeric CDK and CDK bound to a cyclin when simulating nib ("nib": inhibitor...apparently new yippie slang) binding. In this case, the difference is in the water recruitment.

Again, one is reminded of the many subtle factors, including water interactions, that dictate differences between nib binding to different but similar kinases.


  1. Sorry for a little off-topic comment.
    I was redirected by KP to older post:

    Basically, I am curious how to interpret the biochemical data for Sunitinib.

    It is widely cited (I can supply few reviews/original papers) as having Ki for PDGFR of 10 nM and IC50 for the same receptor in cell equal to 10 nM ! I find that very strange since Sunitinib is a typical ATP competitive inhibitor and K.Shokat cites PDGFR KM of 15uM.
    That should mean IC50 of almost 800nM in cell assay !

    Moreover, Ki and cell IC50 values for other tyrosine kinases are also practically identical. Very interesting, I think.

  2. Oleg, cell IC50 of 10 nM is fantastic. Can you cite a ref or two which I can look up?
    IF the Ki and IC50s for TKs are almost identical, either Km values must be adjusted for the [ATP (to make the ratio one)], or assuming constant [ATP], Km values for ATP must be the same and equal to [ATP]. Interesting.

  3. I first noticed this reading advanced publication in Nature Reviews Drug Discovery:


    original publications is this one:


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