We pursue a multi-dimensional approach towards deciphering and quantifying weak intermolecular interactions in chemical and biological systems. Experimental study in this research involves the investigation of protein-ligand interactions, synthetic host-guest complexation, and dynamic processes in designed unimolecular model systems, such as molecular torsion balances. It is complemented by computational analysis and exhaustive data base mining in the Cambridge Crystallographic Database (CSD) and the Protein Data Bank (PDB). The findings from this comprehensive investigation greatly aid structure-based drug design. Examples of intermolecular interactions quantified by this approach are orthogonal dipolar interactions, organofluorine interactions, π-stacking on peptide bonds, cation-π interactions, halogen bonding, and chalcogen bonding. Extensive protein and small-molecule crystallographic work is essential to all study. The lecture will first present the influence of substituent effects on aromatic π-π stacking interactions. Orthogonal dipolar interactions involving C–F bonds, discovered in a fluorine scan of inhibitors of thrombin, a serine protease from the blood coagulation cascade, will be discussed. Halogen bonding and chalcogen bonding are introduced and shown to be potent interactions both in synthetic model systems and protein-ligand complexes formed by the cysteine protease human Cathepsin L (hCatL). A highlight is the formation of supramolecular capsules based solely on halogen-bonding interactions. The formation of enantiopure resorcin[4]arene-based cage receptors with four chiral alleno-acetylenic chiral walls is presented. Chiral substituted cyclohexanes are complexed with complete enantioselectivity, resulting solely from dispersion interactions and perfect shape complementarity and, in the case of halocyclohexanes, also from halogen-bonding interactions. Highly stable complexes are formed by endo- and exo-tropines which undergo very strong hydrogen bonding to the four-fold O–H...O hydrogen-bonding array closing the cages.

Molecular recognition studies to advance structure-based drug design

256th National Meeting (2018)

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