Much ado about protein dynamics
Let me alert you, in case you haven't noticed, to the latest issue of Science which is a special issue on protein dynamics.
There is much of merit here, but this article is especially relevant to drug discovery. It talks about the interaction of small molecules and how it reshapes the energy landscape of protein conformational motion. One of the most useful ways of thinking about small molecule-protein interactions is to visualize a protein that fluctuates between several conformational states which are in equilibrium. A small molecule can inhibit the protein by preferentially stabilizing one of these states.
The article illustrates this concept with several examples, most notably inhibition of kinases. Many kinases exist in an inactive and active state and kinase inhibitors stabilize and block one of these states. Such conformational trapping can also reduce mobility of the protein. The article also describes how certain kinase inhibitors such as imatinib and nilotinib trap the kinase in the inactive state while others such as dasatinib trap it in an active state. Although all three of these are classified as ATP-competitive inhibitors, dasatinib blocks the Abl-Bcr kinase by effecting an allosteric movement of a particular loop. Allosteric inhibitors of kinases are of value since they won't target the highly conserved ATP-binding site, thus reducing problems with selectivity. But allosteric targeting is difficult since many times it involves targeting shallow, poorly defined sites including those involved in protein-protein interactions. HTS campaigns aimed at disrupting P-P interactions usually give very poor results. However, recent tools and especially NMR with labeled residues may improve the detection of weakly binding molecules that may be missed in assays (where the limit is usually 30 µM). HSQC spectra are generally taken of the protein, with and without the inhibitor, and changes in residue resonances can give an indication of conformational changes.
In any case, this article and the others are worth reading. Basically it seems that the remodeling of energy landscapes of proteins by either small molecules or other signals is a concept acquiring central traction. Such a concept could essentially tie together the dual problems of protein folding and inhibiting proteins with small molecules.
Lee, G., & Craik, C. (2009). Trapping Moving Targets with Small Molecules Science, 324 (5924), 213-215 DOI: 10.1126/science.1169378