Objective

This presentation highlights the relevance of optimizing binding kinetic signatures within today's medicinal chemistry approaches. A detailed and structure-based understanding of the precise pharmacophoric requirements that influence binding kinetics of small molecules targeted at receptor or enzyme binding sites is a prerequisite to pre-engineer e.g. slow off-rates into novel lead and drug candidates. However, our current knowledge on structure-kinetic relationships is fairly limited since a clear correlation of lead structure elements with kinetic features is often overlaid by conformational changes on the target proteins, thus complicating the interpretation of activity, kinetic, and also selectivity data. We will exemplify the rational design of kinase inhibitors displaying long residence times by pursuing the "retro-design" approach, taking advantage of disrupting the hydrophobic spine topology within the catalytic domain of protein kinases. In addition, HDAC inhibitors will be discussed that utilize a conformational change within the target enzymes that renders those inhibitors to show slow off-rates.