Exploiting ligand and receptor adaptability in rational drug design using dynamics and structure-based strategies

Interactions between a biological macromolecule and a small molecule ligand involve intricate recognition events which are strongly influenced by both structure and dynamics factors. The ligand and receptor must mutually fit and adapt to each other to form a strong complex, and detailed knowledge of these factors would certainly aid drug design efforts. This work describes our experience in the characterization and exploitation of these properties within the context of two medicinal chemistry programs that targeted the essential protease enzymes of the human cytomegalovirus (HCMV) and the hepatitis C virus (HCV). Central to the rational use of such data was the qualitative elucidation of the binding parameters that defined modes/roles of each substituent of the ligands. This required the development of dynamics- and structure-based strategies that logically considered data from structure-activity relationships, NMR spectroscopy, computational chemistry, and X-ray crystallography. An important emphasis was made to monitor the relationship between inhibitor activity and ligand flexibility using C-13 NMR T, relaxation data, within the context of promoting the bioactive conformation as a drug design tool. Besides these methods which focused on data from the ligand perspective, interesting ligand-induced adaptive features of the receptors were also observed, and their impacts on drug design were explored.