6MHD

Glutathione S-Transferase Omega 1 bound to covalent inhibitor 44

Summary for 6MHD

• Entry DOI: 10.2210/pdb6mhd/pdb
• Related: 6MHB 6MHC
• Descriptor: Glutathione S-transferase omega-1, N-[(3-methyl-1,2-oxazol-5-yl)methyl]-N-(4-phenyl-1,3-thiazol-2-yl)propanamide, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (5 entities in total)
• Functional Keywords: transferase, transferase inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 56905.64

Authors

Petrunak, E.M.,Stuckey, J.A. (deposition date: 2018-09-17, release date: 2019-02-20, Last modification date: 2024-10-23)

Primary citation

Dai, W.,Samanta, S.,Xue, D.,Petrunak, E.M.,Stuckey, J.A.,Han, Y.,Sun, D.,Wu, Y.,Neamati, N.
Structure-Based Design of N-(5-Phenylthiazol-2-yl)acrylamides as Novel and Potent Glutathione S-Transferase Omega 1 Inhibitors.
J. Med. Chem., 62:3068-3087, 2019

PubMed Abstract: Using reported glutathione S-transferase omega 1 (GSTO1-1) cocrystal structures, we designed and synthesized acrylamide-containing compounds that covalently bind to Cys32 on the catalytic site. Starting from a thiazole derivative 10 (GSTO1-1 IC = 0.6 μM), compound 18 was synthesized and cocrystallized with GSTO1. Modification on the amide moiety of hit compound 10 significantly increased the GSTO1-1 inhibitory potency. We solved the cocrystal structures of new derivatives, 37 and 44, bearing an amide side chain bound to GSTO1. These new structures showed a reorientation of the phenyl thiazole core of inhibitors, 37 and 44, when compared to 18. Guided by the cocrystal structure of GSTO1:44, analogue 49 was designed, resulting in the most potent GSTO1-1 inhibitor (IC = 0.22 ± 0.02 nM) known to date. We believe that our data will form the basis for future studies of developing GSTO1-1 as a new drug target for cancer therapy.

PubMed: 30735370
DOI: 10.1021/acs.jmedchem.8b01960

Experimental method

X-RAY DIFFRACTION (2.16 Å)