Cappelli Andrea, Nannicini Chiara, Chelini Alessia, Paolino Marco, Giuliani Germano, Anzini Maurizio, Giordani Antonio, Sabatini Chiara, Caselli Gianfranco, Mennuni Laura, Makovec Francesco, Giorgi Gianluca, Vomero Salvatore, Menziani Maria Cristina
Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
Bioorg Med Chem Lett. 2016 Nov 1;26(21):5160-5163. doi: 10.1016/j.bmcl.2016.10.001. Epub 2016 Oct 4.
Two new fluorophenylindenone derivatives were designed as potential p38α 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.
通过保留邻位吡啶/氟苯基药效团与酶蛋白的关键相互作用，设计了两种新的氟苯基茚满二酮衍生物作为潜在的p38α丝裂原活化蛋白激酶调节剂。有趣的是，这两种氟苯基茚满二酮异构体表现出不同的活性，化合物6表现为抑制剂，而化合物5则表现为假定的激活剂。通过对接研究和分子动力学模拟，根据DFG环的稳定性对这些结果进行了合理解释，化合物5以一种更易于磷酸化的构象实现了DFG环的稳定。
