Caseinolytic Protein Protease Case Study

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The caseinolytic protein protease (ClpP) is a highly conserved serine protease present in bacteria and higher organisms. ClpP is responsible for cell homeostasis and among other duties for the regulation of bacterial virulence in several pathogens including Staphylococcus aureus and Listeria monocytogenes. Significant interests in ClpP inactivation started with the discovery of its crucial role in virulence of these pathogens that cause severe infections in the clinics and are difficult to treat through the occurrence of multidrug resistance .
There have been efforts to discover and develop small molecules that perturb the activities of ClpP.Stephan A. Sieber etc. demonstrated that selective inhibition of ClpP in Staphylococcus aureus resulted in a drastically decreased expression of major virulence factors.To date, β-lactone is the main inhibitor scaffold that exhibits specificity for ClpP, it is important to systematically analyze the structural features and expand the chemical space of putative inhibitors.
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Stephan A. Sieber, we developed a workflow (shown in Fig 1) based on the structural information of these β-lactones and ClpP protease. Two pharmacophore models was generated based on HYPOGEN and HipHop method respectively. Because of the structural oneness, we combined two pharmacophore models artificially to expand the features and validated by the training set and decoy set. Meanwhile, we extracted the bioactive molecular fingerprints to generate de novo compound library to expand the scaffold. The workflow consisting of various methods provided a feasible solution for discovery of novel potential ClpP protease inhibitors and theoretical basis for further optimization of hit

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