Trends in Peptide and Protein Sciences (Sep 2017)
Evaluating the Difficulty involved in Designing Small Molecule Drugs to Inhibit Protein-Protein Interactions
Abstract
The targeting of drugs to block protein-protein interactions (PPIs) has attracted great interest over recent years. Such targets, however, have been held to be difficult to inhibit using low molecular weight compounds, and as a consequence they are often branded as “undruggable”. This is partly because the interfaces involved are seen to be large, and the fact that they are generally regarded as being too smooth and too flat. In the work reported here, a series of quantitative systematic studies have been performed to determine the molecular area, roughness, curvature, and amino acid composition of the interfacial surfaces of PPIs, to determine the feasibility of designing small molecule drugs to inhibit these interactions. The X-ray crystal structures are analysed for a set of 48 PPIs involving G-protein, membrane receptor extracellular domain, and enzyme-inhibitor complexes. The protein partners involved in these PPIs are shown to have much larger interfacial areas than those for protein-small molecule complexes (≥ 900 Å2 vs ~250 Å2, respectively), and they have interfaces that are fairly smooth (with fractal dimensions close to 2) and quite flat (with mean surface curvatures in the order of ± 0.1 Å-1). The mean interfacial surface curvatures of the PPI protein partners, however, are seen to change upon complexation, some very significantly so. Despite the fact that the amino acid compositions of the PPI interface surfaces are found to be significantly different from that of the average protein surface (with variations according to the type of PPI), it is concluded that the prospects for designing low molecular weight PPI inhibitors that act in an orthosteric manner remain rather limited. HIGHLIGHTS •Mean interfacial surface curvatures have been determined for protein-protein interaction (PPI) partners in their complexed and uncomplexed states. •Mean interfacial surface roughnesses have been determined for protein-protein interaction (PPI) partners in their complexed and uncomplexed states. •Amino acid compositions have been determined for PPI interface surfaces and these compared with that for the average protein surface. •Quantification of the PPI interfacial surface properties is used to assess the druggability of these targets.
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