Organic Chemistry Seminar

We pursue in a multi-dimensional approach the quantification of weak intermolecular interactions in chemical and biological systems. Examples discussed in the lecture are orthogonal dipolar interactions, organofluorine interactions, substituent effects on π-π-stacking interactions, halogen bonding, and chalcogen bonding. Enantioselective complexation based solely on dispersion interactions and perfect shape complementarity is achieved with new chiral alleno-acetylenic cage compounds. We also explore the energetics of the replacement of conserved water molecules in protein co-crystal structures by ligand parts, with a particular interest in cyclic water clusters. Lessons learned are directly applicable to ligand design and optimization in drug discovery and crop protection research, but equally to the assembly of synthetic supramolecular systems.

The approach is illustrated in examples taken from our structure-based drug design projects. Specific examples for investigations of protein-ligand interactions include (i) addressing the Gly-rich ATP-triphosphate-binding loop of protein kinase A (PKA), (ii) complexation at the allosteric site of IspD, an enzyme from the non-mevalonate pathway of isoprenoid biosynthesis and deciphering of the allosteric mechanism, (iii) halogen-bonding at the active site of the cysteine protease hCatL, and (iv) ligand development against a novel target for antimalarials, serine hydroxymethyl transferase (SHMT), a key enzyme from the folate biosynthesis cycle.