With the rise of antibiotic-resistant bacteria, there is an urgent need to develop antibacterials with new mechanisms of action. Because of its essential role in bacterial survival and the possibility to induce unselective substrate degradation via activation by small molecules, ClpP is an interesting target. Given the small number of chemotypes known to target ClpP ant the limited understanding of protein-ligand interactions involved in the binding of ClpP activators, we sought to develop a computational approach to provide insight into specific ligand-ClpP interactions and address some of the structure optimization issues in the field.