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Common Structural Features of Hydrophobic α-Helical Hot Spots: Insights for the Design of Novel α-Helix Mimetics
Shelby R Kell1,2, Zhen Wang1,2, Haitao Ji1,2,3
1Drug Discovery Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, United States.
Abstract:
The binding conformations of α-helical hydrophobic hot spots are convergent into two spatial areas in protein-protein complex structures. The physical basis for convergence was disclosed, which allows the development of pharmacophore models for i/i + 4/i + 7 or i/i + 3/i + 4 α-helical hot spots. Further investigation revealed that this convergence of binding conformations is common among all hydrophobic hot spots regardless of their α-helical positions. This observation led to a streamlined generation of pharmacophore models for hydrophobic hot spots at any positions along the α-helix. These successfully evaluated pharmacophore models may be useful for designing novel α-helical hot spot mimetics.
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