Document Detail


Alkylation of a catalytic aspartate group of the SIV protease by an epoxide inhibitor.
MedLine Citation:
PMID:  9416419     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Specific irreversible inhibition of the SIV protease by FMOC-protected piperidine epoxide 1 involves alkylation of the protein. Tryptic digestion of the alkylated protein and mass spectrometric analysis of the peptides identify an active site aspartic acid (Asp-25) as the single residue that is alkylated. Computer modeling of 1 bound in the crystal structure of the SIV protease using DOCK 3.5 indicates that 1 has appropriate access to the active site. It is able to align in an orientation that allows a proton to be transferred to the epoxide from one of the catalytic aspartic acid groups in conjunction with nucleophilic attack on the epoxide of the carboxylate moiety of the second catalytic aspartic acid residue. Hydrophobic interactions are not optimal for this process due, in part, to the rigidity of the inhibitor ring system and the planar conformation of the amide. The combination of modeling with protein alkylation can provide insights into structural modifications of the inhibitor that may lead to improved inhibitory activity.
Authors:
P S Caldera; Z Yu; R M Knegtel; F McPhee; A L Burlingame; C S Craik; I D Kuntz; P R Ortiz de Montellano
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  5     ISSN:  0968-0896     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  1997 Nov 
Date Detail:
Created Date:  1998-02-09     Completed Date:  1998-02-09     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  2019-27     Citation Subset:  IM; X    
Affiliation:
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco 94143-0446, USA.
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MeSH Terms
Descriptor/Qualifier:
Alkylation / drug effects
Antiviral Agents / pharmacology*
Aspartic Acid / drug effects,  metabolism*
Aspartic Acid Endopeptidases / antagonists & inhibitors*,  metabolism*
Catalysis
Enzyme Activation / drug effects
Epoxy Compounds / pharmacology*
Mass Spectrometry
Models, Molecular
Protease Inhibitors / pharmacology*
Simian immunodeficiency virus / enzymology*
Grant Support
ID/Acronym/Agency:
ES04705/ES/NIEHS NIH HHS; GM39552/GM/NIGMS NIH HHS; RR01614/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Antiviral Agents; 0/Epoxy Compounds; 0/Protease Inhibitors; 56-84-8/Aspartic Acid; EC 3.4.23.-/Aspartic Acid Endopeptidases; EC 3.4.23.-/SIV(mac) proteinase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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