19501-33-8Relevant academic research and scientific papers
Rapid Discovery of Aspartyl Protease Inhibitors Using an Anchoring Approach
ünver, M. Yagiz,Camacho, Carlos Jamie,D?mling, Alexander,Haupenthal, J?rg,Heine, Andreas,Hirsch, Anna K. H.,Jumde, Varsha R.,Klebe, Gerhard,Konstantinidou, Markella,Magari, Francesca,Sutanto, Fandi
, (2020)
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.
MODULATORS OF TNF- ALPHA SIGNALLING
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Paragraph 0066, (2016/08/03)
The present invention provides compounds which are modulators of TNF-alpha signaling and methods of use thereof for treating a patient having a TNF-alpha mediated condition. The compounds can be represented by the following structural formulas:
