Robert Bergman Lecture: Molecular Recognition in Chemical and Biological Systems: Chemical Models and Biostructural Investigations
Seminar | October 8 | 11 a.m.-12 p.m. | 120 Latimer Hall
We pursue a multi-disciplinary approach to quantify weak intermolecular interactions in chemical and biological systems. Examples discussed in this lecture are orthogonal dipolar interactions, organofluorine interactions, substituent effects on π-π-stacking interactions, halogen bonding, and chalcogen bonding. Supramolecular capsules assembled from designed resorcinarene-based hemispheres, which exclusively associate either by multivalent halogen bonding or chalcogen bonding interactions, are reported and provide new perspectives to the field of encapsulation. Complete enantioselective complexation of (±)-trans-1,2-dimethylcyclohexane, which binds in the higher-energy diaxial conformation, is achieved with new chiral alleno-acetylenic cage receptors. Remarkably, chiral recognition is based solely on dispersion interactions and perfect shape complementarity. 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. In complexes of alleno-acetylenic cages with alcohol guests, circular fourfold, five-fold, and six-fold HO-bonding networks with one handedness are observed. These alcohol networks closely resemble the water networks seen in protein structures. Lessons learned from these studies 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) halogen-bonding at the active site of the cysteine protease hCatL, and (iii) ligand development against a novel target for antimalarials, serine hydroxymethyl transferase (SHMT), a key enzyme from the folate biosynthesis cycle. These examples demonstrate the relevance of (a) molecular recognition understanding for structure-based design, (b) competent synthesis, and (c) accurate conformational analysis for successful small-molecule drug discovery projects.