期刊
CHEMMEDCHEM
卷 15, 期 8, 页码 680-684出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202000024
关键词
hydrazine-tetrazoles; MCR chemistry; docking protocol; aspartic protease; crystal structures
资金
- ITN Accelerated Early stage drug dIScovery (AEGIS) [675555]
- US National Institutes of Health (NIH) [2R01GM097082-05]
- European Lead Factory (IMI) [115489]
- Qatar National Research Foundation [NPRP6-065-3-012]
- COFUNDs ALERT [665250]
- Prominent [754425]
- KWF Kankerbestrijding grant [10504]
- European Research Council (ERC) [757913]
- Helmholtz Association's Initiative and Networking Fund, COFUNDs ALERT [665250]
Pharmacophore searches that include anchors, fragments contributing above average to receptor binding, combined with one-step syntheses are a powerful approach for the fast discovery of novel bioactive molecules. Here, we are presenting a pipeline for the rapid and efficient discovery of aspartyl protease inhibitors. First, we hypothesized that hydrazine could be a multi-valent warhead to interact with the active site Asp carboxylic acids. We incorporated the hydrazine anchor in a multicomponent reaction and created a large virtual library of hydrazine derivatives synthetically accessible in one-step. Next, we performed anchor-based pharmacophore screening of the libraries and resynthesized top-ranked compounds. The inhibitory potency of the molecules was finally assessed by an enzyme activity assay and the binding mode confirmed by several soaked crystal structures supporting the validity of the hypothesis and approach. The herein reported pipeline of tools will be of general value for the rapid generation of receptor binders beyond Asp proteases.
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