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Development of a potent 2-oxoamide inhibitor of secreted phospholipase A2 guided by molecular docking calculations and molecular dynamics simulations.

Abstract：

: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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Vasilakaki S,Barbayianni E,Leonis G,Papadopoulos MG,Mavromoustakos T,Gelb MH,Kokotos G

doi

10.1016/j.bmc.2016.02.040

subject

Has Abstract

pub_date

2016-04-15 00:00:00

pages

1683-95

issue

8

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(16)30130-4

journal_volume

24

pub_type

杂志文章

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