@phdthesis{Heilos2019,
  author    = {Heilos, Anna},
  title     = {Mechanistic Insights into the Inhibition of Cathepsin B and Rhodesain with Low-Molecular Inhibitors},
  doi       = {10.25972/OPUS-17822},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-178228},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {Cysteine proteases play a crucial role in medical chemistry concerning various fields reaching from more common ailments like cancer and hepatitis to less noted tropical diseases, namely the so-called African Sleeping Sickness (Human Arfican Trypanosomiasis). Detailed knowledge about the catalytic function of these systems is highly desirable for drug research in the respective areas. In this work, the inhibition mechanisms of the two cysteine proteases cathepsin B and rhodesain with respectively one low-molecular inhibitor class were investigated in detail, using computational methods. In order to sufficiently describe macromolecular systems, molecular mechanics based methods (MM) and quantum mechanical based method (QM), as well as hybrid methods (QM/MM) combining those two approaches, were applied. For Cathespin B, carbamate-based molecules were investigated as potential inhibitors for the cysteine protease. The results indicate, that water-bridged proton-transfer reactions play a crucial role for the inhibition. The energetically most favoured pathway (according to the calculations) includes an elimination reaction following an E1cB mechanism with a subsequent carbamylation of the active site amino acid cysteine. Nitroalkene derivatives were investigated as inhibitors for rhodesain. The investigation of structurally similar inhibitors showed, that even small steric differences can crucially influence the inhibition potential of the components. Furthermore, the impact of a fluorination of the nitroalkene inhibitors on the inhibition mechanism was investigated. According to experimental data measured from the working group of professor Schirmeister in Mainz, fluorinated nitroalkenes show - in contrast to the unfluorinated compounds - a time dependent inhibition efficiency. The calculations of the systems indicate, that the fluorination impacts the non-covalent interactions of the inhibitors with the enzymatic environment of the enzyme which results in a different inhibition behaviour.},
  subject      = {Cysteinproteasen},
  language  = {en}
}