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 no vel chemical type identified by high throughput screening. The compound spe cifically inhibits the chymotrypsin-like catalytic activity of the human pr oteasome with an IC50 value in the micromolar range. Using the crystal stru cture of the yeast proteasome we modeled the structure of the human proteas ome 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 th e inhibitor having enhanced stacking/hydrophobic interactions with the enzy me. One order of magnitude in inhibitory potency was gained. (C) 2001 Elsev ier Science Ltd. All rights reserved.