Development of potent inhibitors of the bacterial RNA polymerase for the treatment of infections with Mycobacterium tuberculosis
The RNA polymerase (RNAP) is a very large enzyme with a molecular weight of about 400 kDa. It consists of several subunits: the catalytically active core enzyme and the sigma factor. These two complexes interact with each other during transcription.
Two approaches are followed with the aim to discover potent RNAP inhibitors. One approach focuses on a direct inhibition of the core enzyme. Due to the fact that both the three-dimensional structures as well as inhibition mechanisms of the RNAP are well-known, we currently apply computer-aided drug design and virtual screening. In a second step, virtual hits are tested in order to characterize their effectiveness in vitro. The next step involves chemical optimization on the basis of established structure activity supported by virtual drug design.
The goal of the second approach is to prevent the interaction of the core enzyme and the sigma factors. We could already identify first screening hits and now focus on the improvement of the screening hits regarding their potency and pharmacological properties. By that, we want to develop a highly potent drug that can be therapeutically applied in humans.
- Drug Design and Optimization - Prof. Dr. Rolf W. Hartmann