Modeling of the binding mode of a non-covalent inhibitor of the 20S proteasome.: Application to structure-based analogue design

The 2-aminobenzylstatine derivative 1 is a 20S proteasome inhibitor of a novel chemical type identified by high throughput screening. The compound specifically inhibits the chymotrypsin-like catalytic activity of the human proteasome with an IC50 value in the micromolar range. Using the crystal structure of the yeast proteasome we modeled the structure of the human proteasome in complex with 1. As one of the first applications of the model in our oncology programme targeting the proteasome, we designed an analogue of the inhibitor having enhanced stacking/hydrophobic interactions with the enzyme. One order of magnitude in inhibitory potency was gained. (C) 2001 Elsevier Science Ltd. All rights reserved.