期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 13, 期 10, 页码 1670-1677出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.2c00296
关键词
Protein-protein interactions; Small-molecule inhibitors; PPI hot spots; alpha-Helix mimetics
资金
- Moffitt Chemical Biology Core through the NIH/NCI-designated comprehen-sive cancer center grant [P30-CA76292]
The study reveals a convergence of binding conformations of alpha-helical hydrophobic hot spots in protein-protein complex structures, regardless of the position along the helix. This observation streamlines the development of pharmacophore models and may be useful for the design of novel alpha-helical hot spot mimetics.
The binding conformations of alpha-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 alpha-helical hot spots. Further investigation revealed that this convergence of binding conformations is common among all hydrophobic hot spots regardless of their alpha-helical positions. This observation led to a streamlined generation of pharmacophore models for hydrophobic hot spots at any positions along the alpha-helix. These successfully evaluated models be useful for novel alpha-helical hot mimetics.
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