A Step toward NRF2‐DNA Interaction Inhibitors by Fragment‐Based NMR Methods
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- Опубліковано 19 чер 2022
- Sven Brüschweiler presented their recent work in collaboration with Boehringer Ingelheim on the characterization of ligand-target interactions through utilization of NMR methods in early stages of drug discovery. After computational assessment of intrinsically disordered parts of the protein, 1,800 fragment molecules were screened against the Neh1-ΔLZIP domain of NRF2. 1H-15N HSQC was used to observe shifts of target amide groups, including those of asparagine and glutamine, identifying two hits based on chemical shift perturbations. infiniSee was used to search for analogs of the phenyl carboxylic acid scaffold in Enamine’s REAL Space in a “SAR-by-catalog” approach.
35 compounds were discovered; 27 came from the Boehringer Ingelheim and Sigma Aldrich libraries, and eight were purchased from Enamine. The set allowed SAR elucidation of the compound series.
1H-15N HSQC was subsequently used to identify the ligand binding site and a crystal structure was resolved. Second step data-driven docking calculations resulted in three docking clusters complemented by chemical shift changes for the complex structures indicating exchanging conformations due to weak binding.
BioSolveIT DrugSpace 2022 "It's a small world"
Speaker: Sven Brüschweiler (MAG-LAB) - Наука та технологія
