An efficient strategy for digging protein-protein interactions for rational drug design - A case study with HIF-1α/VHL.
Eur J Med Chem
; 227: 113871, 2022 Jan 05.
Article
em En
| MEDLINE
| ID: mdl-34638033
ABSTRACT
The ubiquitination of the hypoxia-inducible factor-1α (HIF-1α) is mediated by interacting with the von Hippel-Lindau protein (VHL), and is associated with cancer, chronic anemia, and ischemia. VHL, an E3 ligase, has been reported to degrade HIF-1 for decades, however, there are few successful inhibitors currently. Poor understanding of the binding pocket and a lack of in-depth exploration of the interactions between two proteins are the main reasons. Hence, we developed an effective strategy to identify and design new inhibitors for protein-protein interaction targets. The hydroxyproline (Hyp564) of HIF-1α contributed the key interaction between HIF-1α and VHL. In this study, detailed information of the binding pocket were explored by alanine scanning, site-directed mutagenesis and molecular dynamics simulations. Interestingly, we found the interaction(s) between Y565 and H110 played a key role in the binding of VHL/HIF-1α. Based on the interactions, 8 derivates of VH032, 16a-h, were synthesized by introducing various groups bounded to H110. Further assay on protein and cellular level exhibited that 16a-h accessed higher binding affinity to VHL and markable or modest improvement in stabilization of HIF-1α or HIF-1α-OH in HeLa cells. Our work provides a new orientation for the modification or design of VHL/HIF-1α protein-protein interaction inhibitors.
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MEDLINE
Assunto principal:
Desenho de Fármacos
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Proteína Supressora de Tumor Von Hippel-Lindau
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Subunidade alfa do Fator 1 Induzível por Hipóxia
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Hidroxiprolina
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article