Common Structural Features of Hydrophobic α-Helical Hot Spots: Insights for the Design of Novel α-Helix Mimetics

25 August 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


The binding conformations of hydrophobic α-helical hot spots are convergent into two spatial areas in protein–protein interaction (PPI) complex structures. The physical basis for convergence was disclosed, which enables the generation 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 α-helical hot spots regardless of 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 for regulations of α-helix-mediated PPIs.


Protein-protein interactions
small-molecule inhibitors
PPI hot spots
α-helix mimetics

Supplementary materials

the Supporting Information
The supporting information for this manuscript


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