Document Detail

Inhibition of secreted phospholipases A₂ by 2-oxoamides based on α-amino acids: Synthesis, in vitro evaluation and molecular docking calculations.
MedLine Citation:
PMID:  21216150     Owner:  NLM     Status:  MEDLINE    
Group IIA secreted phospholipase A₂ (GIIA sPLA₂) is a member of the mammalian sPLA₂ enzyme family and is associated with various inflammatory conditions. In this study, the synthesis of 2-oxoamides based on α-amino acids and the in vitro evaluation against three secreted sPLA₂s (GIIA, GV and GX) are described. The long chain 2-oxoamide GK126 based on the amino acid (S)-leucine displayed inhibition of human and mouse GIIA sPLA₂s (IC₅₀ 300nM and 180nM, respectively). It also inhibited human GV sPLA₂ with similar potency, while it did not inhibit human GX sPLA₂. The elucidation of the stereoelectronic characteristics that affect the in vitro activity of these compounds was achieved by using a combination of simulated annealing to sample low-energy conformations before the docking procedure, and molecular docking calculations.
Varnavas D Mouchlis; Victoria Magrioti; Efrosini Barbayianni; Nathan Cermak; Rob C Oslund; Thomas M Mavromoustakos; Michael H Gelb; George Kokotos
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-12-16
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  19     ISSN:  1464-3391     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-01-17     Completed Date:  2011-05-03     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  735-43     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Ltd. All rights reserved.
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MeSH Terms
Amino Acids / chemical synthesis,  chemistry*,  pharmacology
Binding Sites
Catalytic Domain
Computer Simulation
Enzyme Inhibitors / chemical synthesis,  chemistry*,  pharmacology
Phospholipases A2, Secretory / antagonists & inhibitors*,  metabolism
Pyridines / chemistry*
Grant Support
HL36235/HL/NHLBI NIH HHS; R01 AI054384/AI/NIAID NIH HHS; R01 AI054384-21/AI/NIAID NIH HHS; R01 CA052874/CA/NCI NIH HHS; R01 CA052874-12/CA/NCI NIH HHS; R01 HL036235/HL/NHLBI NIH HHS; R01 HL036235-21/HL/NHLBI NIH HHS; R01 HL050040/HL/NHLBI NIH HHS; R01 HL050040-18/HL/NHLBI NIH HHS; R37 HL036235/HL/NHLBI NIH HHS; R37 HL036235-27/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Amino Acids; 0/Enzyme Inhibitors; 0/Pyridines; 713-05-3/oxoamide; EC A2, Secretory

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