title: Modeling of the binding mode of a non-covalent inhibitor of the 20S proteasome. Application to structure-based analogue design.
abstract: The 2-aminobenzvlstatine derivative I 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.
authors.affiliation: Oncology Research, Novartis Pharmaceuticals Inc, Basel, Switzerland. pascal.furet@pharma.novartis.com
authors.forename: P
authors.initials: P
authors.lastname: Furet
authors.forename: P
authors.initials: P
authors.lastname: Imbach
authors.forename: P
authors.initials: P
authors.lastname: Fürst
authors.forename: M
authors.initials: M
authors.lastname: Lang
authors.forename: M
authors.initials: M
authors.lastname: Noorani
authors.forename: J
authors.initials: J
authors.lastname: Zimmermann
authors.forename: C
authors.initials: C
authors.lastname: García-Echeverria
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D009842:Oligopeptides; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C013165:statine