2ohs

From Proteopedia

Revision as of 13:25, 23 January 2008

X-ray crystal structure of beta secretase complexed with compound 6b

Overview

Fragment-based lead discovery has been successfully applied to the, aspartyl protease enzyme beta-secretase (BACE-1). Fragment hits that, contained an aminopyridine motif binding to the two catalytic aspartic, acid residues in the active site of the enzyme were the chemical starting, points. Structure-based design approaches have led to identification of, low micromolar lead compounds that retain these interactions and, additionally occupy adjacent hydrophobic pockets of the active site. These, leads form two subseries, for which compounds 4 (IC50 = 25 muM) and 6c, (IC50 = 24 muM) are representative. In the latter series, further, optimization has led to 8a (IC50 = 690 nM).

About this Structure

2OHS is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Memapsin 2, with EC number 3.4.23.46 Full crystallographic information is available from OCA.

Reference

Application of Fragment Screening by X-ray Crystallography to the Discovery of Aminopyridines as Inhibitors of beta-Secretase., Congreve M, Aharony D, Albert J, Callaghan O, Campbell J, Carr RA, Chessari G, Cowan S, Edwards PD, Frederickson M, McMenamin R, Murray CW, Patel S, Wallis N, J Med Chem. 2007 Feb 22;. PMID:17315857

Page seeded by OCA on Wed Jan 23 15:25:31 2008