Structural analysis of PI3-kinase isoforms: Identification of residues enabling selective inhibition by small molecule ATP-competitive inhibitors

2008 ◽  
Vol 477 (2) ◽  
pp. 404-410 ◽  
Author(s):  
Marketa J. Zvelebil ◽  
Michael D. Waterfield ◽  
Stephen J. Shuttleworth
Keyword(s):  
Structural Analysis ◽  
Small Molecule ◽  
Selective Inhibition ◽  
Pi3 Kinase ◽  
Competitive Inhibitors

scholarly journals Structural analysis of human dual-specificity phosphatase 22 complexed with a phosphotyrosine-like substrate

2015 ◽  
Vol 71 (2) ◽  
pp. 199-205 ◽  
Author(s):  
George T. Lountos ◽  
Scott Cherry ◽  
Joseph E. Tropea ◽  
David S. Waugh
Keyword(s):  
Crystal Structure ◽  
Structural Analysis ◽  
Phosphatase Activity ◽  
Small Molecule ◽  
Molecular Basis ◽  
Protein Tyrosine Phosphatases ◽  
Simple Method ◽  
Dual Specificity Phosphatase ◽  
Dual Specificity ◽  
Nitrophenyl Phosphate

4-Nitrophenyl phosphate (p-nitrophenyl phosphate, pNPP) is widely used as a small molecule phosphotyrosine-like substrate in activity assays for protein tyrosine phosphatases. It is a colorless substrate that upon hydrolysis is converted to a yellow 4-nitrophenolate ion that can be monitored by absorbance at 405 nm. Therefore, the pNPP assay has been widely adopted as a quick and simple method to assess phosphatase activity and is also commonly used in assays to screen for inhibitors. Here, the first crystal structure is presented of a dual-specificity phosphatase, human dual-specificity phosphatase 22 (DUSP22), in complex with pNPP. The structure illuminates the molecular basis for substrate binding and may also facilitate the structure-assisted development of DUSP22 inhibitors.

scholarly journals Structural Analysis of Small-Molecule Binding to the BAZ2A and BAZ2B Bromodomains

ChemMedChem ◽  
2018 ◽  
Vol 13 (14) ◽  
pp. 1479-1487 ◽  
Author(s):  
Andrea Dalle Vedove ◽  
Dimitrios Spiliotopoulos ◽  
Vito G. D'Agostino ◽  
Jean-Rémy Marchand ◽  
Andrea Unzue ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Small Molecule

scholarly journals Discovery and Design of Novel Small Molecule GSK-3 Inhibitors Targeting the Substrate Binding Site

2020 ◽  
Vol 21 (22) ◽  
pp. 8709
Author(s):  
Ido Rippin ◽  
Netaly Khazanov ◽  
Shirley Ben Joseph ◽  
Tania Kudinov ◽  
Eva Berent ◽  
...  
Keyword(s):  
Binding Site ◽  
Small Molecule ◽  
Substrate Binding ◽  
Pharmacophore Model ◽  
Drug Induced ◽  
Substrate Binding Site ◽  
Zinc Database ◽  
Competitive Inhibitors ◽  
Ic50 Values ◽  
Critical Binding

The serine/threonine kinase, GSK-3, is a promising drug discovery target for treating multiple pathological disorders. Most GSK-3 inhibitors that were developed function as ATP competitive inhibitors, with typical limitations in specificity, safety and drug-induced resistance. In contrast, substrate competitive inhibitors (SCIs), are considered highly selective, and more suitable for clinical practice. The development of SCIs has been largely neglected in the past because the ambiguous, undefined nature of the substrate-binding site makes them difficult to design. In this study, we used our previously described structural models of GSK-3 bound to SCI peptides, to design a pharmacophore model and to virtually screen the “drug-like” Zinc database (~6.3 million compounds). We identified leading hits that interact with critical binding elements in the GSK-3 substrate binding site and are chemically distinct from known GSK-3 inhibitors. Accordingly, novel GSK-3 SCI compounds were designed and synthesized with IC50 values of~1–4 μM. Biological activity of the SCI compound was confirmed in cells and in primary neurons that showed increased β-catenin levels and reduced tau phosphorylation in response to compound treatment. We have generated a new type of small molecule GSK-3 inhibitors and propose to use this strategy to further develop SCIs for other protein kinases.

Abstract 322: Selective inhibition of MYC expression by a small molecule G-quadruplex stabilizer

2016 ◽  
Author(s):  
Elena C. Leon ◽  
John K. Simmons ◽  
David Calabrese ◽  
Wendy DuBois ◽  
Kenneth Felsenstein ◽  
...  
Keyword(s):  
Small Molecule ◽  
Selective Inhibition ◽  
G Quadruplex

scholarly journals Structural Analysis of a Novel Small Molecule Ligand Bound to the CXCL12 Chemokine

2014 ◽  
Vol 57 (22) ◽  
pp. 9693-9699 ◽  
Author(s):  
Emmanuel W. Smith ◽  
Yan Liu ◽  
Anthony E. Getschman ◽  
Francis C. Peterson ◽  
Joshua J. Ziarek ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Small Molecule ◽  
Small Molecule Ligand

scholarly journals KDM4B as a Target for Prostate Cancer: Structural Analysis and Selective Inhibition by a Novel Inhibitor

2014 ◽  
Vol 57 (14) ◽  
pp. 5975-5985 ◽  
Author(s):  
Chia-Han Chu ◽  
Ling-Yu Wang ◽  
Kai-Cheng Hsu ◽  
Chung-Chin Chen ◽  
Hsing-Hung Cheng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Structural Analysis ◽  
Selective Inhibition

scholarly journals Structural analysis of metalloform-selective inhibition of methionine aminopeptidase

2006 ◽  
Vol 62 (4) ◽  
pp. 425-432 ◽  
Author(s):  
Sheng-Xue Xie ◽  
Wei-Jun Huang ◽  
Ze-Qiang Ma ◽  
Min Huang ◽  
Robert P. Hanzlik ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Selective Inhibition ◽  
Methionine Aminopeptidase
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