Binding of the anticancer prodrug CB1954 to the activating enzyme NQO2 revealed by the crystal structure of their complex

Majed AbuKhader; John Heap; Cristina De Matteis; Barrie Kellam; Stephen W Doughty; Nigel Minton; Massimo Paoli

doi:10.1021/jm050730n

Binding of the anticancer prodrug CB1954 to the activating enzyme NQO2 revealed by the crystal structure of their complex

J Med Chem. 2005 Dec 1;48(24):7714-9. doi: 10.1021/jm050730n.

Authors

Majed AbuKhader¹, John Heap, Cristina De Matteis, Barrie Kellam, Stephen W Doughty, Nigel Minton, Massimo Paoli

Affiliation

¹ School of Pharmacy and The Institute of Infection, Immunity and Inflammation, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.

PMID: 16302811
DOI: 10.1021/jm050730n

Abstract

CB1954 is an attractive prodrug for directed-enzyme prodrug therapy (DEPT) and a conventional prodrug against tumors in which the enzyme NQO2 is highly expressed. We have determined the crystal structure of the NQO2-CB1954 complex to 2.0 A resolution. The binding of the prodrug is governed by hydrophobic forces, while two key electrostatic contacts determine the specific orientation of the ligand. The structure also reveals an unfavorable interaction, therefore suggesting possible avenues for DEPT-tailored engineering studies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry*
Aziridines / chemistry*
Crystallization
Crystallography, X-Ray
Models, Molecular
Molecular Conformation
Prodrugs / chemistry*
Protein Binding
Quinone Reductases / chemistry*

Substances

Antineoplastic Agents
Aziridines
Prodrugs
tretazicar
NRH - quinone oxidoreductase2
Quinone Reductases