Document Detail

Theoretical study on the mechanism of a ring-opening reaction of oxirane by the active-site aspartic dyad of HIV-1 protease.
MedLine Citation:
PMID:  18175006     Owner:  NLM     Status:  MEDLINE    
Two possible mechanisms of the irreversible inhibition of HIV-1 protease by epoxide inhibitors are investigated on an enzymatic model using ab initio (MP2) and density functional theory (DFT) methods (B3LYP, MPW1K and M05-2X). The calculations predict the inhibition as a general acid-catalyzed nucleophilic substitution reaction proceeding by a concerted SN2 mechanism with a reaction barrier of ca. 15-21 kcal mol(-1). The irreversible nature of the inhibition is characterized by a large negative reaction energy of ca. -17-(-24) kcal mol(-1). A mechanism with a direct proton transfer from an aspartic acid residue of the active site onto the epoxide ring has been shown to be preferred compared to one with the proton transfer from the acid catalyst facilitated by a bridging catalytic water molecule. Based on the geometry of the transition state, structural data important for the design of irreversible epoxide inhibitors of HIV-1 protease were defined. Here we also briefly discuss differences between the epoxide ring-opening reaction in HIV-1 protease and epoxide hydrolase, and the accuracy of the DFT method used.
Juraj Kóna
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Publication Detail:
Type:  Journal Article     Date:  2007-12-06
Journal Detail:
Title:  Organic & biomolecular chemistry     Volume:  6     ISSN:  1477-0520     ISO Abbreviation:  Org. Biomol. Chem.     Publication Date:  2008 Jan 
Date Detail:
Created Date:  2008-01-04     Completed Date:  2008-04-03     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  101154995     Medline TA:  Org Biomol Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  359-65     Citation Subset:  IM    
International School for Advanced Studies (SISSA) and Democritos Modeling Center for Research in Atomistic Simulation (INFM), via Beirut 2-4, 34014 Trieste, Italy.
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MeSH Terms
Aspartic Acid / chemistry
Binding Sites
Epoxide Hydrolases / antagonists & inhibitors,  chemistry
Epoxy Compounds / chemistry*,  pharmacology
Ethylene Oxide / chemistry*,  pharmacology
HIV Protease / chemistry*,  drug effects
HIV Protease Inhibitors / chemistry*,  pharmacology
Hydrogen Bonding
Models, Chemical*
Models, Molecular
Molecular Structure
Quantum Theory*
Structure-Activity Relationship
Reg. No./Substance:
0/Epoxy Compounds; 0/HIV Protease Inhibitors; 56-84-8/Aspartic Acid; 75-21-8/Ethylene Oxide; EC 3.3.2.-/Epoxide Hydrolases; EC 3.4.23.-/HIV Protease; EC 3.4.23.-/p16 protease, Human immunodeficiency virus 1

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