I was reading this review and came by this:

Direct pharmacologic inhibition of RAS has been a major challenge. Interference with the nucleotide-binding pocket of the protein seems to be far more difficult than interfering with the analogous ATP-binding pocket in kinases. This is presumably due to the much higher (picomolar) affinity of RAS for GTP.

What is meant by affinity? How do inhibitors work (in this context)? Kindly help me as to what does this mean, I am new to biochemistry.

  • $\begingroup$ It is a paid subscription, but still here is the link nature.com/nrd/journal/v13/n12/full/nrd4281.html $\endgroup$ Commented Aug 28, 2016 at 13:27
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    $\begingroup$ There is a section with a non-mathematical description of Receptor/ligand binding affinity in the Wikipedia entry for Ligand, and a numerical approach in Alberts et al. — especially Fig.3-44. The treatment of protein inhibitors in textbooks is usually done in relation to enzymes, which are more complex than other binding proteins. However the section on competitive inhibitors in Wikipedia, for example, is relevant to other proteins. $\endgroup$
    – David
    Commented Aug 29, 2016 at 9:31
  • $\begingroup$ I have edited your title to make it appropriate to the specific question you have asked about inhibition of Ras (note conventional capitalization). This makes for better indexing, should others have a similar question later. $\endgroup$
    – David
    Commented Aug 29, 2016 at 12:24

1 Answer 1


Protein binding interactions are usually referred to by how easily the binding partner can be displaced by something other than the preferred substrate. Usually, this is in reference to the concentration of the binding partner required such that the average occupancy of the protein (in this case RAS) to the binding partner is ~ 50%.

If the affinity protein for a given binding partner is in the picomolar range, that means that it binds so tightly that very very little substrate is needed to achieve 50% occupancy. In order to interfere with RAS's preference for GTP, you would have to design something that RAS likes to bind to with even greater preference that would be able to displace GTP. This has proven quite challenging.

Other kinases, whose affinity for their substrate is not nearly as high, have been easier to design molecules that displace their endogenous ligands and hence interfere with their function.

I know it is Wiki, but the activation/deactivation section of this Page provides some insight into how RAS binds GTP and turned on, how GAP functions to help RAS hydrolyze GTP->GDP, resulting in turning off RAS downstream signalling. RAS signalling is actually a balance between Guanine nucleotide exchange factors causing RAS to drop GDP for GTP (turning RAS on) and GTPase activating proteins mentioned above (GAP).

Mutated RAS in cancer often involves a coding change such that the ability to hydrolyze GTP->GDP is mitigated, thus leaving RAS in the ON state.

For your initial question of inhibitors (and more general). Cellular signalling involves the interaction of proteins with other proteins and/or signalling molecules and/or DNA/RNA. Very generically, inhibitors interfere with this interaction.

Example: Kinases add a phosphate group to another protein, that can among other things change the affinity of that protein for its binding partners, and thus set off a downstream signalling cascade. If kinase A phosphorylates protein 1, and you inhibit kinase A from doing this, you have inhibited downstream effects from protein 1's signalling cascade.

Take a look at this picture: The two drugs in red interfere with downstream signalling cascades in B-cell receptor signalling by preventing endogenous binding/signalling events.

enter image description here


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