Synthetic Molecules Probing Biomolecule Recognition, Mechanisms, and Function
The aim of this study is to achieve a deeper fundamental understanding of molecular recognition mechanisms in biological systems.
Specific objectives; the study proposes to use design and synthesis of organic molecules to: 1.systematically study solvation thermodynamics of protein-ligand interactions 2.systematically study ligand-induced changes in protein conformational entropy 3.characterize halogen bonding and fluorine dipolar interactions in galectin-ligand complexes.
4.use knowledge from aims 1-3 to design selective and efficient inhibitors of cancer and inflammation-related human galectin proteins 5.use galectin inhibitors as tools for deciphering the mechanisms behind galectins controlling protein localization, trafficking and sorting, as well as to correlate this with effects on a cellular and organismal level related to inflammation and cancer 6.use knowledge from aims 1-3 to design selective and efficient malarial dihydroorotate dehydrogenase (DHODH) inhibitors.
Emphasis of this study is on poorly understood entropic alterations upon protein-ligand interactions, i.e. solvation and protein conformational entropy alterations, and on interactions involving halogen atoms. Understanding gained will be exploited in the design of a) synthetic molecules specifically probing cellular and biomolecular mechanisms of how cancer- and inflammation-related human galectins control localization and trafficking of other proteins and in design of b) optimized inhibitors of the malaria dihydroorotate dehydrogenase enzyme co-factor site.