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Review
. 2015 Jun 18;22(6):689-703.
doi: 10.1016/j.chembiol.2015.04.019.

Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions

Luca Laraia  1 , Grahame McKenzie  2 , David R Spring  3 , Ashok R Venkitaraman  2 , David J Huggins  4
Affiliations
Review

Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions

Luca Laraia et al. Chem Biol. .

Abstract

Protein-protein interactions (PPIs) underlie the majority of biological processes, signaling, and disease. Approaches to modulate PPIs with small molecules have therefore attracted increasing interest over the past decade. However, there are a number of challenges inherent in developing small-molecule PPI inhibitors that have prevented these approaches from reaching their full potential. From target validation to small-molecule screening and lead optimization, identifying therapeutically relevant PPIs that can be successfully modulated by small molecules is not a simple task. Following the recent review by Arkin et al., which summarized the lessons learnt from prior successes, we focus in this article on the specific challenges of developing PPI inhibitors and detail the recent advances in chemistry, biology, and computation that facilitate overcoming them. We conclude by providing a perspective on the field and outlining four innovations that we see as key enabling steps for successful development of small-molecule inhibitors targeting PPIs.

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Figures

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Graphical abstract
Figure 1
Figure 1
Distributions of Ligand Efficiency and Lipophilic Ligand Efficiency Bar graphs showing the distributions of (A) ligand efficiency (LE) and (B) lipophilic ligand efficiency (LLE) using IC50 data for 1,736 small molecules in the TIMBAL database of PPI inhibitors and 37,143 small-molecule inhibitors in the curated portion of the BindingDB database. Heavy atom counts and cLogP values were computed using Schrödinger's Qikprop, and the small molecules were prepared using Schrödinger's Ligprep.
Figure 2
Figure 2
Apo Protein Structures of Six Surfaces Involved in PPIs, Showing Clashes with Ligands Overlaid from Protein-Ligand Complex Structures The apo and holo structures were aligned using residues within 5.0 Å of the ligand, and the heavy atom root-mean-square deviation (RMSD) of these residues was calculated. (A) Bcl-XL from PDB: 1R2D overlaid with the ligand from PDB: 2O2N. The protein surface is shaded in orange and the RMSD is 1.51 Å. (B) IL-2 from PDB: 1PY2 overlaid with the ligand from PDB: 3INK. The protein surface is shaded in cyan and the RMSD is 1.12 Å. (C) HDM2 from PDB: 1Z1M overlaid with the ligand from PDB: 4IPF. The protein surface is shaded in magenta and the RMSD is 1.49 Å. (D) Keap1 from PDB: 1ZGK overlaid with the ligand from PDB: 4IFN. The protein surface is shaded in yellow and the RMSD is 0.40 Å. (E) HIV integrase from PDB: 1EX4 overlaid with the ligand from PDB: 4CE9. The protein surface is shaded in purple and the RMSD is 0.76 Å. (F) KRas from PDB: 3GFT overlaid with the ligand from PDB: 4EPY. The protein surface is shaded in pink and the RMSD is 1.02 Å. The ligands are displayed using CPK atom coloring in all cases.
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