Development of a potent 2-oxoamide inhibitor of secreted phospholipase A(2) guided by molecular docking calculations and molecular dynamics simulations

Inhibition of group IIA secreted phospholipase A(2) (GIIA sPLA(2)) 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 sPLA(2)s. Herein, the development of new potent inhibitors b...

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Published inBioorganic & medicinal chemistry Vol. 24; no. 8; pp. 1683 - 1695
Main Authors Vasilakaki, Sofia, Barbayianni, Efrosini, Leonis, Georgios, Papadopoulos, Manthos G., Mavromoustakos, Thomas, Gelb, Michael H., Kokotos, George
Format Journal Article
LanguageEnglish
Published OXFORD Elsevier 15.04.2016
Subjects
Biochemistry & Molecular Biology
Chemistry
Chemistry, Medicinal
Chemistry, Organic
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Physical Sciences
Science & Technology
GROUP-V
GROUP-X
DESIGN
EMERGING ROLES
Molecular dynamics
2-Oxoamides
FREE-ENERGIES
Inhibitors
Secreted phospholipase A
AMBER
ENZYMES
DISEASE
Docking
COMPLETE SET
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Summary:Inhibition of group IIA secreted phospholipase A(2) (GIIA sPLA(2)) 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 sPLA(2)s. 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 sPLA(2), respectively). In addition, molecular dynamics simulations were employed to shed light on GK241 potent and selective inhibitory activity. (C) 2016 Elsevier Ltd. All rights reserved.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2016.02.040