54679-74-2Relevant academic research and scientific papers
Reversible Inhibitors Arrest ClpP in a Defined Conformational State that Can Be Revoked by ClpX Association
Pahl, Axel,Lakemeyer, Markus,Vielberg, Marie-Theres,Hackl, Mathias W.,Vomacka, Jan,Korotkov, Vadim S.,Stein, Martin L.,Fetzer, Christian,Lorenz-Baath, Katrin,Richter, Klaus,Waldmann, Herbert,Groll, Michael,Sieber, Stephan A.
supporting information, p. 15892 - 15896 (2016/01/29)
Caseinolytic protease P (ClpP) is an important regulator of Staphylococcus aureus pathogenesis. A high-throughput screening for inhibitors of ClpP peptidase activity led to the identification of the first non-covalent binder for this enzyme class. Co-crystallization of the small molecule with S. aureus ClpP revealed a novel binding mode: Because of the rotation of the conserved residue proline 125, ClpP is locked in a defined conformational state, which results in distortion of the catalytic triad and inhibition of the peptidase activity. Based on these structural insights, the molecule was optimized by rational design and virtual screening, resulting in derivatives exceeding the potency of previous ClpP inhibitors. Strikingly, the conformational lock is overturned by binding of ClpX, an associated chaperone that enables proteolysis by substrate unfolding in the ClpXP complex. Thus, regulation of inhibitor binding by associated chaperones is an unexpected mechanism important for ClpP drug development.
ALKALOID AMINOESTER DERIVATIVES AND MEDICINAL COMPOSITION THEREOF
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, (2012/01/12)
The present invention relates to alkaloid aminoester compounds which act as muscarinic receptor antagonists, processes for the preparation of such a compound, compositions which contain such a compound, and therapeutic uses of such a compound.
ALKALOID AMINOESTER DERIVATIVES AND MEDICINAL COMPOSITION THEREOF
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Page/Page column 67, (2012/01/13)
The present invention relates to alkaloid aminoester derivatives acting as muscarinic receptor antagonists, processes for their preparation, compositions comprising them and therapeutic uses thereof.
