Due to Shigellosis, caused by Shigella bacteria, over 200.000 people die per year. Antibiotics are used for treatment but the development of resistance grows. The class-II chaperone IpgC is an essential part of the type-III secretion system, which is used to translocate effector proteins into a target cell. IpgC interacts thereby with many pathogenicity factors and was hence chosen as target for drug design. We determined a high-resolution crystal structure of IpgC, which provided the basis for crystallographic fragment screening. Fragments identified as binders were enlarged via in-silico docking using SeeSAR. Three of the resulting molecules were crystallographically validated as IpgC ligands, with one binding in a natural interaction partner’s binding site. In the current work, these ligands serve as lead structures. The ligands will be enlarged, docked, scored and a similarity scan will be performed. Resulting molecules will then be analysed via X-ray crystallography and in assays.
Johanna intends to achieve the following milestones:
- The three lead structures will be enlarged via SeeSAR Fast-Grow, docked, scored also using SeeSAR. A similarity scan will also be performed.
- Analysis of top scored ligands (X-ray cryst., assays); in SeeSAR: creation of derivatives; enlarge, dock and score similarity scan ligands.
- Analysis of similarity scan ligands (X-ray cryst., assays). Based on results from Milestone 2 further development of hits in SeeSAR.