Clp Model

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

The Common Feature Pharmacophore Generation protocol identifies configurations or three-dimensional spatial arrangements of chemical features that are common to molecules in a training set. The configurations are identified by a pruned exhaustive search, starting with small sets of features and extending them until no larger common configuration is found. 3D QSAR Pharmacophore Generation protocol derives Structure Activity Relationship (SAR) pharmacophore models from a set of molecules which cover a wide range of

Then the Generate Fingerprint Feature protocol in Pipeline Pilot was applied to extract fingerprints and convert them into corresponding molecular fragments. After generating bioisosteres by Enumerate Bioisosteres protocol, the fragments were used to generate a de novo molecular library through the Enumerate from Fragments protocol in DS. Filtering by the Lipinski’s rule of five and the Veber rules, the optimized molecular library was applied to virtual screening by the pharmacophore model.

Virtual screening of small molecule libraries forms one aspect of a sophisticated approach to drug discovery. The final pharmacophore hypothese artificially generated was applied as a 3D structural query for retrieving potent molecules from the de novo library using the Screen Library protocol. For each molecule in the databases, 500 conformers were generated with the fast conformer generation method, allowing a maximum energy of 20 kcal/mol above that of the most stable