| Inhibition of secreted phospholipases A₂ by 2-oxoamides based on α-amino acids: Synthesis, in vitro evaluation and molecular docking calculations. | |
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MedLine Citation:
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PMID: 21216150 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Varnavas D Mouchlis; Victoria Magrioti; Efrosini Barbayianni; Nathan Cermak; Rob C Oslund; Thomas M Mavromoustakos; Michael H Gelb; George Kokotos |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-12-16 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry Volume: 19 ISSN: 1464-3391 ISO Abbreviation: Bioorg. Med. Chem. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2011-01-17 Completed Date: 2011-05-03 Revised Date: 2012-10-09 |
Medline Journal Info:
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Nlm Unique ID: 9413298 Medline TA: Bioorg Med Chem Country: England |
Other Details:
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Languages: eng Pagination: 735-43 Citation Subset: IM |
Copyright Information:
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Copyright © 2011 Elsevier Ltd. All rights reserved. |
Affiliation:
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Department of Chemistry, University of Athens, Greece. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acids
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chemical synthesis,
chemistry*,
pharmacology Animals Binding Sites Catalytic Domain Computer Simulation Enzyme Inhibitors / chemical synthesis, chemistry*, pharmacology Humans Mice Phospholipases A2, Secretory / antagonists & inhibitors*, metabolism Pyridines / chemistry* |
| Grant Support | |
ID/Acronym/Agency:
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HL36235/HL/NHLBI NIH HHS; R01 AI054384-21/AI/NIAID NIH HHS; R01 CA052874-12/CA/NCI NIH HHS; R01 HL036235-21/HL/NHLBI NIH HHS; R01 HL050040-18/HL/NHLBI NIH HHS; R37 HL036235-27/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amino Acids; 0/Enzyme Inhibitors; 0/Pyridines; 713-05-3/oxoamide; EC 3.1.1.4/Phospholipases A2, Secretory |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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