2NT7

Crystal structure of PTP1B-inhibitor complex

Summary for 2NT7

• Entry DOI: 10.2210/pdb2nt7/pdb
• Related: 2H4G 2H4K 2HCE 2HCW 2HCX 2HFA 2NTA
• Descriptor: Tyrosine-protein phosphatase non-receptor type 1, {[5-(3-{[1-(BENZYLSULFONYL)PIPERIDIN-4-YL]AMINO}PHENYL)-4-BROMO-2-(2H-TETRAZOL-5-YL)-3-THIENYL]OXY}ACETIC ACID (3 entities in total)
• Functional Keywords: ptp1b, protein-inhibitor complex, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic side: P18031
• Total number of polymer chains: 1
• Total formula weight: 35453.23

Authors

Xu, W.,Follows, B. (deposition date: 2006-11-07, release date: 2007-04-17, Last modification date: 2023-12-27)

Primary citation

Wan, Z.K.,Follows, B.,Kirincich, S.,Wilson, D.,Binnun, E.,Xu, W.,Joseph-McCarthy, D.,Wu, J.,Smith, M.,Zhang, Y.L.,Tam, M.,Erbe, D.,Tam, S.,Saiah, E.,Lee, J.
Probing acid replacements of thiophene PTP1B inhibitors.
Bioorg.Med.Chem.Lett., 17:2913-2920, 2007

PubMed Abstract: The following account describes our systematic effort to replace one of the carboxylate groups of our diacid thiophene PTP1B inhibitors. Active hits were validated using enzymatic assays before pursuing efforts to improve the potency. Only when the C2 carboxylic acid was replaced with another ionizable functional group was reversible and competitive inhibition retained. Use of a tetrazole ring or 1,2,5-thiadiazolidine-3-one-1,1-dioxide as a carboxylate mimetic led to the discovery of two unique starting series that showed improved permeability (PAMPA) and potency of the order of 300nM. The SAR from these efforts underscores some of the major challenges in developing small molecule inhibitors for PTP1B.

PubMed: 17336064
DOI: 10.1016/j.bmcl.2007.02.043

Experimental method

X-RAY DIFFRACTION (2.1 Å)