2003
DOI: 10.1021/jm034122o
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Fragment Screening and Assembly:  A Highly Efficient Approach to a Selective and Cell Active Protein Tyrosine Phosphatase 1B Inhibitor

Abstract: Using an NMR-based fragment screening and X-ray crystal structure-based assembly, starting with millimolar ligands for both the catalytic site and the second phosphotyrosine binding site, we have identified a small-molecule inhibitor of protein tyrosine phosphatase 1B with low micromolar inhibition constant, high selectivity (30-fold) over the highly homologous T-cell protein tyrosine phosphatase, and good cellular activity in COS-7 cells.

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Cited by 159 publications
(95 citation statements)
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“…These results suggest that increasing the lipophilicity of the B ring improved inhibitory potency against PTP1B. This is consistent with earlier studies in which lipophilic moieties stabilized the enzyme-compound complex via hydrophobic interactions with the active site and surrounding subpockets, a common feature of PTP1B-inhibitor complexes 40,41 . This concept is also supported by our docking simulations described below.…”
Section: Biological Evaluationsupporting
confidence: 91%
“…These results suggest that increasing the lipophilicity of the B ring improved inhibitory potency against PTP1B. This is consistent with earlier studies in which lipophilic moieties stabilized the enzyme-compound complex via hydrophobic interactions with the active site and surrounding subpockets, a common feature of PTP1B-inhibitor complexes 40,41 . This concept is also supported by our docking simulations described below.…”
Section: Biological Evaluationsupporting
confidence: 91%
“…Various approaches to fragment binding detection have been adopted, among them mass spectrometry [81], NMR [82,83], crystallography [84,85] and combinations there-from [86,87]. Special considerations for fragment based discovery using X-ray crystallography include the necessity for obtaining a well characterized crystal form of the target protein which diffracts well (d min < 2.5Å), possesses a lattice amenable to soaking experiments (i.e., without occlusion of the target site), and is able to withstand exposure to modest quantities of organic solvents (e.g., ethanol and DMSO are popular solvents for chemical fragments).…”
Section: Fragment Condensationmentioning
confidence: 99%
“…Such inhibitors often show greatly improved potency and selectivity. 26,27 Other peripheral residues, such as Arg47, Asp48, Lys41, Phe52, and Ala27, also can be targeted by extended inhibitors. 14, 16, 17, 28-31 Our research group has recently developed two libraries of extended bidentate PTP inhibitors that are derived from α-ketocarboxylic acids.…”
Section: Ptp Inhibitorsmentioning
confidence: 99%