86539-99-3Relevant academic research and scientific papers
Substrate activity screening: A fragment-based method for the rapid identification of nonpeptidic protease inhibitors
Wood, Warren J. L.,Patterson, Andrew W.,Tsuruoka, Hiroyuki,Jain, Rishi K.,Ellman, Jonathan A.
, p. 15521 - 15527 (2005)
A new fragment-based method for the rapid development of novel and distinct classes of nonpeptidic protease inhibitors, Substrate Activity Screening (SAS), is described. This method consists of three steps: (1) a library of N-acyl aminocoumarins with diverse, low molecular weight N-acyl groups is screened to identify protease substrates using a simple fluorescence-based assay, (2) the identified N-acyl aminocoumarin substrates are optimized by rapid analogue synthesis and evaluation, and (3) the optimized substrates are converted to inhibitors by direct replacement of the aminocoumarin with known mechanism-based pharmacophores. The SAS method was successfully applied to the cysteine protease cathepsin S, which is implicated in autoimmune diseases. Multiple distinct classes of nonpeptidic substrates were identified upon screening an N-acyl aminocoumarin library. Two of the nonpeptidic substrate classes were optimized to substrates with >8000-fold improvements in cleavage efficiency for each class. Select nonpeptidic substrates were then directly converted to low molecular weight, novel aldehyde inhibitors with nanomolar affinity to cathepsin S. This study demonstrates the unique characteristics and merits of this first substrate-based method for the rapid identification and optimization of weak fragments and provides the framework for the development of completely nonpeptidic inhibitors to many different proteases.
Molecular switching in nanospaces
Dube, Henry,Durola, Fabien,Ajami, Dariush,Rebek Jr., Julius
, p. 595 - 603 (2010)
Switching devices that operate on the molecular level lie at the heart of nanomachinery. The energies involved range from scores of kcal/mol during cleavage or formation of covalent bonds to a few kcal/mol when the signals are changes in conformation. Her
Elucidation of the topography of the thapsigargin binding site in the sarco-endoplasmic calcium ATPase
Skytte, Dorthe Mondrup,Moller, Jesper Vuust,Liu, Huizhen,Nielsen, Helle stergren,Svenningsen, Louise Elsa,Jensen, Christina Mernoe,Olsen, Carl Erik,Christensen, Soren Brogger
experimental part, p. 5634 - 5646 (2010/09/14)
Removal of each of the acyl groups of thapsigargin at O-3, O-8 and O-10 significant reduces the affinity of the inhibitors to the SERCA1a pump. Replacement of the acyl groups at O-3 and O-10 with flexible residues could be performed with only a minor decrease of the affinity, whereas introduction of voluminous stiff residues caused dramatic reduction of the affinity. The results can be rationalized on the basis of the interactions of thapsigargin with the SERCA1a pump as revealed from 3D X-ray structural models of thapsigargin bound to the SERCA1a. In conclusion the results confirm and elaborate the previously suggested pharmocophore model of thapsigargin.
