Vasilakaki Sofia, Barbayianni Efrosini, Leonis Georgios, Papadopoulos Manthos G, Mavromoustakos Thomas, Gelb Michael H, Kokotos George
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece.
Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vas. Constantinou Avenue, Athens 11635, Greece.
Bioorg Med Chem. 2016 Apr 15;24(8):1683-95. doi: 10.1016/j.bmc.2016.02.040. Epub 2016 Mar 2.
Inhibition of group IIA secreted phospholipase A2 (GIIA sPLA2) has been an important objective for medicinal chemists. We have previously shown that inhibitors incorporating the 2-oxoamide functionality may inhibit human and mouse GIIA sPLA2s. Herein, the development of new potent inhibitors by molecular docking calculations using the structure of the known inhibitor 7 as scaffold, are described. Synthesis and biological evaluation of the new compounds revealed that the long chain 2-oxoamide based on (S)-valine GK241 led to improved activity (IC50=143 nM and 68 nM against human and mouse GIIA sPLA2, respectively). In addition, molecular dynamics simulations were employed to shed light on GK241 potent and selective inhibitory activity.
抑制IIA族分泌型磷脂酶A2（GIIA sPLA2）一直是药物化学家的重要目标。我们之前已经表明，含有2-氧代酰胺官能团的抑制剂可能会抑制人和小鼠的GIIA sPLA2。在此，描述了以已知抑制剂7的结构为支架，通过分子对接计算开发新型强效抑制剂的过程。新化合物的合成和生物学评价表明，基于（S）-缬氨酸的长链2-氧代酰胺GK241活性有所提高（对人和小鼠GIIA sPLA2的IC50分别为143 nM和68 nM）。此外，还采用了分子动力学模拟来阐明GK241的强效和选择性抑制活性。
