We develop new tools and strategies to enhance and facilitate small molecule drug discovery research, with a focus on structure-based design of ligands for selected enzymes.  In a collaborative program, we identify weak intermolecular interactions and quantify their energetics using both designed protein-ligand complexes and chemical model systems.  Examples are substituent effects on the interactions between aromatic rings, sulfur-p, and cation-p interactions.  With a focus on dipolar interactions, we also quantified orthogonal interactions between bond dipoles, the role of dipolar arrangement in the stacking of aromatic heterocycles on peptide amide bonds, and halogen bonding.  In a third direction, we address the energetically favorable displacement of individual water molecules in water clusters seen in protein-ligand co-crystal structures by ligand substituents.  Using the enhance knowledge on molecular recognition processes in structure-based design, we generate potent small-molecule inhibitors of new enzyme targets, in particular for fighting infectious diseases such as shigellosis, malaria, and african sleeping sickness.

Molecular recognition and structure-based design

247th National Meeting (2014)

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