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Protein-protein interaction
Designing ligands that inhibit protein-protein interactions is a new frontier in the drug discovery arena. It is widely accepted that this therapeutic class is difficult to tackle using traditional approaches because the topology of the binding sites is different to more familiar protein classes such as enzymes and GPCRs. There is emerging evidence to show that certain binding motifs are conserved even in protein-protein interactions, and small molecules that mimic the binding mode of a-helices and b-turns/sheets have shown promise in this area.1
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Helix Mimetic
a-Helices are one of the major secondary structures involved in protein recognition.2 Although terphenyl based a-helix mimetics have been shown to inhibit certain protein-protein interactions, Jacoby suggested that the simpler biphenyl scaffold can function as a helix mimetic by demonstrating that a 2,6,3',5'-tetrasubstituted biphenyl can be superimposed onto the side chains of an a-helix.3,4 Since a 2,3’-disubstituted biphenyl therefore represents one face of an a-helix, we sought a novel alternative to the 2,3’-disubstituted biphenyl scaffold.
Our SoftFocus Helix Mimetic libraries (HM) are based on an a-substituted phenyl cyclopropane which is known to mimic the bioactive conformation of an ortho substituted biphenyl scaffold.5 The novel scaffold and linking groups are designed to be superimposed on a 2,3’-disubstituted biphenyl group and can be similarly overlayed on the backbone of an a-helix.
They are designed to inhibit protein-protein interactions, but can also target other helical recognition motifs such as the pore region of ion channels.
Protein-protein
The design of our SoftFocus b-sheet mimic library PPI01 is based on the cyclin binding groove in the CDK-cyclin complex. The interaction between the protein and both peptidic and non-peptidic inhibitors at this recruitment site has been observed to form a b-sheet-like hydrogen bonding pattern. The library is designed around a novel scaffold that mimics a “b-sheet type” hydrogen bonding pattern, a key motif observed in protein-protein interactions.
1Zinzalla, G., Future Med. Chem., 2009, 1(1), 65-93
2Murray, J. K., Gellman, S. H., PeptideScience, 2007, 68(5), 657
3 Hamilton et al, J. Am. Chem. Soc., 2001, 5382
4Jacoby, E., Bioorg., Med. Chem. Lett., 2002, 891
5Qiao, J. X., et al, Bioorg. Med. Chem. Lett., 2008, 4118
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