Document Detail


Crystal structures of multidrug-resistant HIV-1 protease in complex with two potent anti-malarial compounds.
MedLine Citation:
PMID:  22469467     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Two potent inhibitors (compounds 1 and 2) of malarial aspartyl protease, plasmepsin-II, were evaluated against wild type (NL4-3) and multidrug-resistant clinical isolate 769 (MDR) variants of human immunodeficiency virus type-1 (HIV-1) aspartyl protease. Enzyme inhibition assays showed that both 1 and 2 have better potency against NL4-3 than against MDR protease. Crystal structures of MDR protease in complex with 1 and 2 were solved and analyzed. Crystallographic analysis revealed that the MDR protease exhibits a typical wide-open conformation of the flaps (Gly48 to Gly52) causing an overall expansion in the active site cavity, which, in turn caused unstable binding of the inhibitors. Due to the expansion of the active site cavity, both compounds showed loss of direct contacts with the MDR protease compared to the docking models of NL4-3. Multiple water molecules showed a rich network of hydrogen bonds contributing to the stability of the ligand binding in the distorted binding pockets of the MDR protease in both crystal structures. Docking analysis of 1 and 2 showed a decrease in the binding affinity for both compounds against MDR supporting our structure-function studies. Thus, compounds 1 and 2 show promising inhibitory activity against HIV-1 protease variants and hence are good candidates for further development to enhance their potency against NL4-3 as well as MDR HIV-1 protease variants.
Authors:
Ravikiran S Yedidi; Zhigang Liu; Yong Wang; Joseph S Brunzelle; Iulia A Kovari; Patrick M Woster; Ladislau C Kovari; Deepak Gupta
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-03-24
Journal Detail:
Title:  Biochemical and biophysical research communications     Volume:  421     ISSN:  1090-2104     ISO Abbreviation:  Biochem. Biophys. Res. Commun.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-14     Completed Date:  2012-08-03     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0372516     Medline TA:  Biochem Biophys Res Commun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  413-7     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
Affiliation:
Department of Biochemistry and Molecular Biology, School of Medicine, Wayne State University, 540 E. Canfield Avenue, Detroit, MI 48201, USA. yedidirs@mail.nih.gov
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MeSH Terms
Descriptor/Qualifier:
Antimalarials / chemistry*,  pharmacology
Aspartic Acid Proteases / antagonists & inhibitors,  chemistry*
Crystallography, X-Ray
Drug Resistance, Multiple, Viral*
HIV Protease / chemistry*,  genetics,  metabolism
HIV Protease Inhibitors / chemistry*,  pharmacology
Humans
Oligopeptides / chemistry*,  pharmacology
Pepstatins / chemistry,  pharmacology
Protein Conformation / drug effects
Pyridines / chemistry*,  pharmacology
Grant Support
ID/Acronym/Agency:
AI65294/AI/NIAID NIH HHS; R21 AI065294-01/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Antimalarials; 0/HIV Protease Inhibitors; 0/Oligopeptides; 0/Pepstatins; 0/Pyridines; 11076-29-2/Streptomyces pepsin inhibitor; EC 3.4.-/Aspartic Acid Proteases; EC 3.4.23.-/HIV Protease; EC 3.4.23.-/p16 protease, Human immunodeficiency virus 1
Comments/Corrections

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