Methods for Computer‐Aided Chemical Biology. Part 5: Rationalizing the Selectivity of Cathepsin Inhibitors on the Basis of Molecular Fragments and Topological Feature Distributions
Hany E. A. Ahmed, Jürgen Bajorath · Chemical Biology & Drug Design · 2009
We report a fragment-based approach to analyze the target selectivity of active compounds. Sets of inhibitors were studied having different activity and selectivity for cathepsins, a family of therapeutically relevant thiol proteases. A systematic analysis was carried out of molecular fragments and atom environment features and their frequency of occurrence for compounds with different selectivity. Fragments extracted from target-selective compounds and independently derived topological features were matched and selectivity markers were identified. Because there is only little overlap between selectivity and other compound set markers, combinations of selectivity set markers could be utilized to predict the selectivity of new cathepsin inhibitors.