2bxv

From Proteopedia

Revision as of 15:47, 5 November 2007

DUAL BINDING MODE OF A NOVEL SERIES OF DHODH INHIBITORS

Overview

Human dihydroorotate dehydrogenase (DHODH) represents an important target, for the treatment of hyperproliferative and inflammatory diseases. In the, cell DHODH catalyzes the rate-limiting step of the de novo pyrimidine, biosynthesis. DHODH inhibition results in beneficial immunosuppressant and, antiproliferative effects in diseases such as rheumatoid arthritis. Here, we present high-resolution X-ray structures of human DHODH in complex with, a novel class of low molecular weight compounds that inhibit the enzyme in, the nanomolar range. Some compounds showed an interesting dual binding, mode within the same cocrystal strongly depending on the nature of, chemical substitution. Measured in vitro activity data correlated with the, prevailing mode of binding and explained the observed structure-activity, relationship. Additionally, the X-ray data confirmed the competitive, nature of the inhibitors toward the putative ubiquinone binding site and, will guide structure-based design and synthesis of molecules with higher, activity.

About this Structure

2BXV is a Single protein structure of sequence from Homo sapiens with SO4, ACT, FMN, ORO and 3FT as ligands. Active as Dihydroorotate oxidase, with EC number 1.3.3.1 Structure known Active Site: AC1. Full crystallographic information is available from OCA.

Reference

Dual binding mode of a novel series of DHODH inhibitors., Baumgartner R, Walloschek M, Kralik M, Gotschlich A, Tasler S, Mies J, Leban J, J Med Chem. 2006 Feb 23;49(4):1239-47. PMID:16480261

Page seeded by OCA on Mon Nov 5 17:52:19 2007