PhD defence K. (Kai) Gao

Structure-Based Drug Discovery Aiming at Human-Diseases Related Protein Targets

Drug discovery remains a challenging task in both academic research and the pharmaceutical industry, owning to the fast upgrades to existing methods and the development of new methods that are applied in this field combined with the growing knowledge of disease mechanism from molecular biology. The speed with which a valuable new drug can be found and continue to use in clinics has accelerated rapidly compared to centuries ago.

The thesis of Kai Gao mainly focuses on the early stage of drug discovery aiming at human-diseases related protein targets. Four target proteins are introduced: PfPdxK kinase a protein related to malaria infections, human acute leukemia associated protein Menin and two human arginases involved in cancer. To investigate the interactions between proteins and ligands, we searched for and designed specific peptides, small fragments, or larger compounds to modulate or inhibit the protein targets. The designs were in part based on information gained from protein structures obtained by X-ray diffraction studies and we used fragment-based drug discovery and high throughput screening to screen large compound libraries to discover new binding compounds. Multiple biophysical approaches were used to validate the hits that were found, including differential scanning fluorimetry, microscale thermophoresis, and surface plasmon resonance. These techniques confirmed the hits found from screening and therefore provide a good start for fragment or compound growth index based improvement of the hits and later lead-like compounds optimization in future research.

Promotor: Prof.dr. A.S. Domling