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Title: Potent Antiviral HIV-1 Protease Inhibitor GRL-02031 Adapts to the Structures of Drug Resistant Mutants with Its P1;#8242;-Pyrrolidinone Ring

Abstract

GRL-02031 (1) is an HIV-1 protease (PR) inhibitor containing a novel P1' (R)-aminomethyl-2-pyrrolidinone group. Crystal structures at resolutions of 1.25-1.55 {angstrom} were analyzed for complexes of 1 with the PR containing major drug resistant mutations, PR{sub I47V}, PR{sub L76V}, PR{sub V82A}, and PR{sub N88D}. Mutations of I47V and V82A alter residues in the inhibitor-binding site, while L76V and N88D are distal mutations having no direct contact with the inhibitor. Substitution of a smaller amino acid in PR{sub I47V} and PR{sub L76V} and the altered charge of PR{sub N88D} are associated with significant local structural changes compared to the wild-type PR{sub WT}, while substitution of alanine in PR{sub V82A} increases the size of the S1' subsite. The P1' pyrrolidinone group of 1 accommodates to these local changes by assuming two different conformations. Overall, the conformation and interactions of 1 with PR mutants resemble those of PR{sub WT} with similar inhibition constants in good agreement with the antiviral potency on multidrug resistant HIV-1.

Authors:
; ; ; ; ; ; ; ;  [1];  [2];  [2];  [2]
  1. (GSU)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
OTHERUNIVERSITYNIH
OSTI Identifier:
1047901
Resource Type:
Journal Article
Journal Name:
J. Med. Chem.
Additional Journal Information:
Journal Volume: 55; Journal Issue: (7) ; 04, 2012; Journal ID: ISSN 0022-2623
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ALANINES; AMINO ACIDS; CRYSTAL STRUCTURE; MUTANTS; MUTATIONS; PYRROLIDONES; RESIDUES

Citation Formats

Chang, Yu-Chung E., Yu, XiaXia, Zhang, Ying, Tie, Yunfeng, Wang, Yuan-Fang, Yashchuk, Sofiya, Ghosh, Arun K., Harrison, Robert W., Weber, Irene T., Purdue), GSI), and CDC). Potent Antiviral HIV-1 Protease Inhibitor GRL-02031 Adapts to the Structures of Drug Resistant Mutants with Its P1;#8242;-Pyrrolidinone Ring. United States: N. p., 2012. Web. doi:10.1021/jm300072d.
Chang, Yu-Chung E., Yu, XiaXia, Zhang, Ying, Tie, Yunfeng, Wang, Yuan-Fang, Yashchuk, Sofiya, Ghosh, Arun K., Harrison, Robert W., Weber, Irene T., Purdue), GSI), & CDC). Potent Antiviral HIV-1 Protease Inhibitor GRL-02031 Adapts to the Structures of Drug Resistant Mutants with Its P1;#8242;-Pyrrolidinone Ring. United States. doi:10.1021/jm300072d.
Chang, Yu-Chung E., Yu, XiaXia, Zhang, Ying, Tie, Yunfeng, Wang, Yuan-Fang, Yashchuk, Sofiya, Ghosh, Arun K., Harrison, Robert W., Weber, Irene T., Purdue), GSI), and CDC). Wed . "Potent Antiviral HIV-1 Protease Inhibitor GRL-02031 Adapts to the Structures of Drug Resistant Mutants with Its P1;#8242;-Pyrrolidinone Ring". United States. doi:10.1021/jm300072d.
@article{osti_1047901,
title = {Potent Antiviral HIV-1 Protease Inhibitor GRL-02031 Adapts to the Structures of Drug Resistant Mutants with Its P1;#8242;-Pyrrolidinone Ring},
author = {Chang, Yu-Chung E. and Yu, XiaXia and Zhang, Ying and Tie, Yunfeng and Wang, Yuan-Fang and Yashchuk, Sofiya and Ghosh, Arun K. and Harrison, Robert W. and Weber, Irene T. and Purdue) and GSI) and CDC)},
abstractNote = {GRL-02031 (1) is an HIV-1 protease (PR) inhibitor containing a novel P1' (R)-aminomethyl-2-pyrrolidinone group. Crystal structures at resolutions of 1.25-1.55 {angstrom} were analyzed for complexes of 1 with the PR containing major drug resistant mutations, PR{sub I47V}, PR{sub L76V}, PR{sub V82A}, and PR{sub N88D}. Mutations of I47V and V82A alter residues in the inhibitor-binding site, while L76V and N88D are distal mutations having no direct contact with the inhibitor. Substitution of a smaller amino acid in PR{sub I47V} and PR{sub L76V} and the altered charge of PR{sub N88D} are associated with significant local structural changes compared to the wild-type PR{sub WT}, while substitution of alanine in PR{sub V82A} increases the size of the S1' subsite. The P1' pyrrolidinone group of 1 accommodates to these local changes by assuming two different conformations. Overall, the conformation and interactions of 1 with PR mutants resemble those of PR{sub WT} with similar inhibition constants in good agreement with the antiviral potency on multidrug resistant HIV-1.},
doi = {10.1021/jm300072d},
journal = {J. Med. Chem.},
issn = {0022-2623},
number = (7) ; 04, 2012,
volume = 55,
place = {United States},
year = {2012},
month = {11}
}