Inhibitor binding alters the directions of domain motions in HIV-1 reverse transcriptase

2002 ◽  
Vol 49 (1) ◽  
pp. 61-70 ◽  
Author(s):  
N. Alpay Temiz ◽  
Ivet Bahar
Keyword(s):  
Reverse Transcriptase ◽  
Inhibitor Binding ◽  
Domain Motions ◽  
Hiv 1

scholarly journals Allosteric Suppression of HIV-1 Reverse Transcriptase Structural Dynamics upon Inhibitor Binding

2011 ◽  
Vol 100 (1) ◽  
pp. 144-153 ◽  
Author(s):  
James M. Seckler ◽  
Mary D. Barkley ◽  
Patrick L. Wintrode
Keyword(s):  
Reverse Transcriptase ◽  
Structural Dynamics ◽  
Inhibitor Binding ◽  
Hiv 1

scholarly journals Structure-Activity Analysis of Vinylogous Urea Inhibitors of Human Immunodeficiency Virus-Encoded Ribonuclease H

2010 ◽  
Vol 54 (9) ◽  
pp. 3913-3921 ◽  
Author(s):  
Suhman Chung ◽  
Michaela Wendeler ◽  
Jason W. Rausch ◽  
Greg Beilhartz ◽  
Matthias Gotte ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Single Molecule ◽  
Thiophene Ring ◽  
Rnase H ◽  
Single Molecule Spectroscopy ◽  
Inhibitor Binding ◽  
Structure Activity ◽  
Immunodeficiency Virus ◽  
Definition Of ◽  
Hiv 1

ABSTRACT Vinylogous ureas 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide and N-[3-(aminocarbonyl)-4,5-dimethyl-2-thienyl]-2-furancarboxamide (compounds 1 and 2, respectively) were recently identified to be modestly potent inhibitors of the RNase H activity of HIV-1 and HIV-2 reverse transcriptase (RT). Both compounds shared a 3-CONH2-substituted thiophene ring but were otherwise structurally unrelated, which prevented a precise definition of the pharmacophore. We have therefore examined a larger series of vinylogous ureas carrying amide, amine, and cycloalkane modifications of the thiophene ring of compound 1. While cycloheptane- and cyclohexane-substituted derivatives retained potency, cyclopentane and cyclooctane substitutions eliminated activity. In the presence of a cycloheptane ring, modifying the 2-NH2 or 3-CONH2 functions decreased the potency. With respect to compound 2, vinylogous ureas whose dimethylthiophene ring contained modifications of the 2-NH2 and 3-CONH2 functions were investigated. 2-NH2-modified analogs displayed potency equivalent to or enhanced over that of compound 2, the most active of which, compound 16, reflected intramolecular cyclization of the 2-NH2 and 3-CONH2 groups. Molecular modeling was used to define an inhibitor binding site in the p51 thumb subdomain, suggesting that an interaction with the catalytically conserved His539 of the p66 RNase H domain could underlie inhibition of RNase H activity. Collectively, our data indicate that multiple functional groups of vinylogous ureas contribute to their potencies as RNase H inhibitors. Finally, single-molecule spectroscopy indicates that vinylogous ureas have the property of altering the reverse transcriptase orientation on a model RNA-DNA hybrid mimicking initiation plus-strand DNA synthesis.

Flexible docking of pyridinone derivatives into the non-nucleoside inhibitor binding site of HIV-1 reverse transcriptase

2004 ◽  
Vol 12 (23) ◽  
pp. 6085-6095 ◽  
Author(s):  
José Luis Medina-Franco ◽  
Sergio Rodrı́guez-Morales ◽  
Cecilia Juárez-Gordiano ◽  
Alicia Hernández-Campos ◽  
Jesús Jiménez-Barbero ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Binding Site ◽  
Flexible Docking ◽  
Inhibitor Binding ◽  
Hiv 1
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