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Reaching for high-hanging fruit in drug discovery at protein–protein interfaces

Abstract

Targeting the interfaces between proteins has huge therapeutic potential, but discovering small-molecule drugs that disrupt protein–protein interactions is an enormous challenge. Several recent success stories, however, indicate that protein–protein interfaces might be more tractable than has been thought. These studies discovered small molecules that bind with drug-like potencies to 'hotspots' on the contact surfaces involved in protein–protein interactions. Remarkably, these small molecules bind deeper within the contact surface of the target protein, and bind with much higher efficiencies, than do the contact atoms of the natural protein partner. Some of these small molecules are now making their way through clinical trials, so this high-hanging fruit might not be far out of reach.

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Figure 1: Examples of protein–protein interface hotspots.
Figure 2: Examples of small molecules that inhibit protein–protein interactions.
Figure 3: Four comparisons of how a protein interacts with its natural protein (or peptide) partner and with a synthetic small molecule.
Figure 4: Disruption of TNF by a small molecule.
Figure 5: Relationship between compound potency and size for small molecules that inhibit protein–protein interactions.

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Acknowledgements

We thank M. Keiser for carrying out the similarity ensemble approach analysis, W. DeLano for MacPyMOL movie advice and for providing Fig. 1, M. Arkin and J. Sadowsky for proof-reading the manuscript, and M. Jacobson and B. Shoichet for discussions.

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Correspondence should be addressed to J.A.W. (jim.wells@ucsf.edu).

Supplementary information

Supplementary Movie 1

Molecular morph (interpolation) between X-ray structures of IL-2 with IL-2Rα bound (PDB 1Z92) and with the small molecule SP4206 bound (PDB 1PY2). IL-2 is shown as spheres, and IL-2Rα and SP4206 are shown in cartoon and stick representation. The contact surface (atoms within 4.5 Å) of each binding partner on IL-2 is shown in green, with particular hydrogen-bonding heavy atoms shown in blue (nitrogen) or red (oxygen); atoms that are not part of the contact surface are shown in grey. The small molecule is shown in yellow, with nitrogen in blue and oxygen in red. Note how the small molecule intercalates into a concave pocket in IL-2 that is closed when IL-2Rα is bound. This movie was created using MacPyMOL (http://www.pymol.org) and RigiMOL (http://www.delanoscientific.com/rigimol.html). (MOV 7137 kb)

Supplementary Movie 2

Molecular morph (interpolation) between NMR structures of Bcl-XL with BAD-derived peptide bound (PDB 1G5J), with small-molecule fragments bound (PDB 1YSG), with compound 31 bound (PDB 1YSI) and with an ABT-737 analogue bound (PDB 2O2N). Compounds are shown in this order (starting with the peptide and finishing with the peptide). Bcl-XL is shown as spheres, and the BAD-derived peptide and small molecules are shown in stick representation. The contact surface of each binding partner on Bcl-XL is shown in green, with particular hydrogen-bonding heavy atoms shown in dark blue (nitrogen) or red (oxygen); atoms that are not part of the contact surface are shown in grey. The small-molecule fragments, small molecules and peptide are shown in yellow (except the ABT-737 analogue, which is shown in light blue), with nitrogen in dark blue, oxygen in red and fluorine in grey. Note the similarities and differences between the biphenyl small-molecule fragment and the analogous parts of more-optimized inhibitors (compound 31 and the ABT-737 analogue). Also note how the ABT-737 analogue buries a hydrophobic, aromatic ring in a pocket that is not seen in the other structures. This movie was created using MacPyMOL (http://www.pymol.org) and RigiMOL (http://www.delanoscientific.com/rigimol.html). (MOV 7417 kb)

Supplementary Movie 3

Molecular morph (interpolation) between X-ray structures of HDM2 with a p53-derived peptide bound (PDB 1YCR), with the small molecule Nutlin-2 bound (PDB 1RV1), and with a benzodiazepinedione (small molecule) bound (PDB 1T4E). Compounds are shown in this order (starting with the peptide and finishing with the peptide). HDM2 is shown as spheres, and the peptide and small molecules are shown in stick representation. The contact surface of each binding partner on HDM2 is shown in green, with particular hydrogen-bonding heavy atoms in blue (nitrogen) or red (oxygen); atoms that are not part of the contact surface are shown in grey. The small molecules and peptide are shown in yellow, with nitrogen in blue, oxygen in red. Note how the aromatic halides of the small molecules (chlorine in green and iodine in purple) project more deeply into HDM2 than do the side chains of the p53-derived peptide. Also, observe how HDM2 presents a more-convex binding surface for the small molecules than it does for the peptide. This movie was created using MacPyMOL (http://www.pymol.org) and RigiMOL (http://www.delanoscientific.com/rigimol.html). (MOV 10073 kb)

Supplementary Movie 4

Molecular morph (interpolation) between X-ray structures of the transactivation domain of E2 from HPV11 with no ligand bound (PDB 1R6K) and with the small molecule compound 18 bound (PDB 1R6N). HPV11 E2 is shown as spheres, and the small molecule is shown in stick representation. The contact surface of the small molecule on E2 is shown in green, with particular hydrogen-bonding heavy atoms in blue (nitrogen); atoms that are not part of the contact surface are shown in grey. The small molecule is shown in yellow, with nitrogen in blue, oxygen in red and chlorine in green. Only the deep-binding pose from the crystal structure is shown, because the protein–small-molecule complex was shown to involve only one small molecule per HPV11 E2 molecule in solution. Note how the small molecule binds to a pocket that is closed in the unbound E2 structure. This movie was created using MacPyMOL (http://www.pymol.org) and RigiMOL (http://www.delanoscientific.com/rigimol.html). (MOV 3474 kb)

Supplementary Movie 5

Molecular morph (interpolation) between X-ray structures of ZipA with FtsZ-derived peptide bound (PDB 1F47), with a fragment (hexahydroquinolizinone) bound (PDB 1S1J), with compound 1 bound (PDB 1Y2F), and with compound 3 bound (PDB 1Y2G). Compounds are shown in this order (starting with the peptide and finishing with the peptide). ZipA is shown as spheres, and the FtsZ-derived peptide and the small molecules are shown in stick representation. Dashed lines indicate hydrogen bonds. The contact surface of each binding partner on ZipA is shown in green, with particular hydrogen-bonding heavy atoms in blue (nitrogen) or red (oxygen); atoms that are not part of the contact surface are shown in grey. The small-molecule fragment, small molecules and peptide are shown in yellow, with nitrogen in blue, oxygen in red and chlorine in green. Medicinal-chemistry efforts starting from the fragment and from compound 1 did not achieve the desired potency, but a computational scaffold-hopping method yielded compound 3, which was selected for future development67. This movie was created using MacPyMOL (http://www.pymol.org) and RigiMOL (http://www.delanoscientific.com/rigimol.html). (MOV 7769 kb)

Supplementary Movie 6

Molecular morph (interpolation) between X-ray structures of the TNF trimer (PDB 1TNF) and the TNF dimer with the small molecule SP304 bound (PDB 2AZ5). The TNF dimer is shown as spheres, and the protein partner (in this case, the third monomer of TNF) and the small molecule are shown in cartoon and stick representation. The contact surface of each binding partner on TNF is shown in green, with particular hydrogen-bonding contact heavy atoms in blue (nitrogen) or red (oxygen); atoms that are not part of the contact surface are shown in grey. The small molecule is shown in yellow, with nitrogen in blue and oxygen in red. SP304 disrupts the TNF trimer interface and increases the rate at which monomers dissociate from the trimer. Note how SP304 binds deeper within the groove of the TNF dimer than does the third monomer of TNF. Observe how the trifluoromethyl group (fluorine in grey) on the small molecule binds within a deep pocket that is closed in the trimer interface. This movie was created using MacPyMOL (http://www.pymol.org) and RigiMOL (http://www.delanoscientific.com/rigimol.html). (MOV 5552 kb)

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Wells, J., McClendon, C. Reaching for high-hanging fruit in drug discovery at protein–protein interfaces. Nature 450, 1001–1009 (2007). https://doi.org/10.1038/nature06526

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