Phenylindenone isomers as divergent modulators of p38α MAP kinase

被引：4

作者：

Cappelli, Andrea ^{[1
,2
]}

Nannicini, Chiara ^{[1
,2
]}

Chelini, Alessia ^{[1
,2
]}

Paolino, Marco ^{[1
,2
]}

Giuliani, Germano ^{[1
,2
]}

Anzini, Maurizio ^{[1
,2
]}

Giordani, Antonio ^{[3
]}

Sabatini, Chiara ^{[3
]}

Caselli, Gianfranco ^{[3
]}

Mennuni, Laura ^{[3
]}

Makovec, Francesco ^{[3
]}

Giorgi, Gianluca ^{[1
,2
]}

Vomero, Salvatore ^{[1
,2
]}

Menziani, Maria Cristina ^{[4
]}

机构：

[1] Univ Siena, Dipartimento Biotecnol Chim & Farm, Via A Moro 2, I-53100 Siena, Italy

[2] Univ Siena, European Res Ctr Drug Discovery & Dev, Via A Moro 2, I-53100 Siena, Italy

[3] Rottapharm Biotech Srl, Via Valosa 3, I-20900 Monza, Italy

[4] Univ Modena & Reggio Emilia, Dipartimento Sci Chim & Geol, Via Campi 103, I-41125 Modena, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 21期

关键词：

MAPK; Kinases; Synthesis; Docking; P38; INHIBITORS; DISEASE; ACTIVATION; SUBSTRATE; MECHANISM; DYNAMICS; COMPLEX; TARGET; BETA;

D O I：

10.1016/j.bmcl.2016.10.001

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Two new fluorophenylindenone derivatives were designed as potential p38 alpha, MAPK modulators by preserving the key interactions of the vicinal pyridine/fluorophenyl pharmacophore with the enzyme protein. Interestingly, these two fluorophenylindenone isomers showed divergent activities, with compound 6 behaving as an inhibitor and 5 as a putative activator. These results were rationalized by docking studies and molecular dynamics simulations in terms of stabilization of DFG loop, by compound 5 in a conformation more accessible to phosphorylation. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：5160 / 5163

页数：4

共 18 条

[1] A Comprehensive Structural Overview of p38 MAPK in Complex with TypeI Inhibitors [J].