Navigating high-dimensional activity landscapes: design and application of the ligand-target differentiation map

The transformation of high-dimensional bioactivity spaces into activity landscape representations is as of yet an unsolved problem in computational medicinal chemistry. High-dimensional activity spaces result from the experimental evaluation of compound sets on large numbers of targets. We introduce a first concept to represent and navigate high-dimensional activity landscapes that is based on a data structure termed ligand-target differentiation (LTD) map. This approach is designed to reduce the complexity of high-dimensional bioactivity spaces and enable the identification and further analysis of compound subsets with interesting activity and structural relationships. Its utility has been demonstrated using a set of more than 1400 inhibitors with exact activity measurements for varying numbers of 172 kinases.