4HXQ

Crystal structure of human Arginase-1 complexed with inhibitor 14

Summary for 4HXQ

• Entry DOI: 10.2210/pdb4hxq/pdb
• Related: 1D3V 2AEB 4HWW 4HZE
• Descriptor: Arginase-1, [(5R)-5-carboxy-5-(methylamino)-7-(piperidin-1-yl)heptyl](trihydroxy)borate(1-), MANGANESE (II) ION, ... (4 entities in total)
• Functional Keywords: metalloenzyme, alpha/beta fold, hydrolase, arginine metabolism, manganese, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 68701.85

Authors

Cousido-Siah, A.,Mitschler, A.,Ruiz, F.X.,Whitehouse, D.L.,Golebiowski, A.,Ji, M.,Zhang, M.,Beckett, P.,Sheeler, R.,Andreoli, M.,Conway, B.,Mahboubi, K.,Schroeter, H.,Van Zandt, M.C.,Podjarny, A. (deposition date: 2012-11-12, release date: 2013-03-20, Last modification date: 2023-09-20)

Primary citation

Van Zandt, M.C.,Whitehouse, D.L.,Golebiowski, A.,Ji, M.K.,Zhang, M.,Beckett, R.P.,Jagdmann, G.E.,Ryder, T.R.,Sheeler, R.,Andreoli, M.,Conway, B.,Mahboubi, K.,D'Angelo, G.,Mitschler, A.,Cousido-Siah, A.,Ruiz, F.X.,Howard, E.I.,Podjarny, A.D.,Schroeter, H.
Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury.
J.Med.Chem., 56:2568-2580, 2013

PubMed Abstract: Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure-activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.

PubMed: 23472952
DOI: 10.1021/jm400014c

Experimental method

X-RAY DIFFRACTION (1.45 Å)