Molecular Modeling Calculations of HIV-1 Reverse Transcriptase Nonnucleoside Inhibitors:  Correlation of Binding Energy with Biological Activity for Novel 2-Aryl-Substituted Benzimidazole Analogues

2003 ◽  
Vol 46 (10) ◽  
pp. 1940-1947 ◽  
Author(s):  
Marilyn B. Kroeger Smith ◽  
Brian M. Hose ◽  
Arie Hawkins ◽  
James Lipchock ◽  
David W. Farnsworth ◽  
...  
Keyword(s):  
Biological Activity ◽  
Molecular Modeling ◽  
Binding Energy ◽  
Reverse Transcriptase ◽  
Nonnucleoside Inhibitors ◽  
Hiv 1

ChemInform Abstract: Synthesis and Biological Activity of Novel Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase. 2-Aryl-Substituted Benzimidazoles.

ChemInform ◽  
2010 ◽  
Vol 29 (20) ◽  
pp. no-no
Author(s):  
T. ROTH ◽  
M. L. MORNINGSTAR ◽  
P. L. BOYER ◽  
S. H. HUGHES ◽  
R. W. JUN. BUCKHEIT ◽  
...  
Keyword(s):  
Biological Activity ◽  
Reverse Transcriptase ◽  
Nonnucleoside Inhibitors ◽  
Hiv 1

scholarly journals Synthesis, Biological Activity, and Crystal Structure of Potent Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase That Retain Activity against Mutant Forms of the Enzyme†

2007 ◽  
Vol 50 (17) ◽  
pp. 4003-4015 ◽  
Author(s):  
Marshall L. Morningstar ◽  
Thomas Roth ◽  
David W. Farnsworth ◽  
Marilyn Kroeger Smith ◽  
Karen Watson ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Biological Activity ◽  
Reverse Transcriptase ◽  
Nonnucleoside Inhibitors ◽  
Mutant Forms ◽  
Hiv 1

Synthesis and Biological Activity of Novel Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase. 2-Aryl-Substituted Benzimidazoles

1997 ◽  
Vol 40 (26) ◽  
pp. 4199-4207 ◽  
Author(s):  
Thomas Roth ◽  
Marshall L. Morningstar ◽  
Paul L. Boyer ◽  
Stephen H. Hughes ◽  
Robert W. Buckheit, ◽  
...  
Keyword(s):  
Biological Activity ◽  
Reverse Transcriptase ◽  
Nonnucleoside Inhibitors ◽  
Hiv 1

scholarly journals Molecular modeling studies of HIV-1 reverse transcriptase nonnucleoside inhibitors: Total energy of complexation as a predictor of drug placement and activity

1995 ◽  
Vol 4 (10) ◽  
pp. 2203-2222 ◽  
Author(s):  
Marilyn B. Kroeger Smith ◽  
Stephen H. Hughes ◽  
Paul L. Boyer ◽  
Christopher J. Michejda ◽  
Carol A. Rouzer ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Reverse Transcriptase ◽  
Total Energy ◽  
Modeling Studies ◽  
Molecular Modeling Studies ◽  
Nonnucleoside Inhibitors ◽  
Hiv 1

scholarly journals Novel Nonnucleoside Inhibitors That Select Nucleoside Inhibitor Resistance Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase

2006 ◽  
Vol 50 (8) ◽  
pp. 2772-2781 ◽  
Author(s):  
Zhijun Zhang ◽  
Michelle Walker ◽  
Wen Xu ◽  
Jae Hoon Shim ◽  
Jean-Luc Girardet ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus ◽  
Nonnucleoside Inhibitors ◽  
Rt Inhibitors ◽  
Hiv 1 ◽  
M184v Mutation

ABSTRACT Mutations in and around the catalytic site of the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) are associated with resistance to nucleoside RT inhibitors (NRTIs), whereas changes in the hydrophobic pocket of the RT are attributed to nonnucleoside RT inhibitor (NNRTI) resistance. In this study, we report a novel series of nonnucleoside inhibitors of HIV-1, exemplified by VRX-329747 and VRX-413638, which inhibit both NNRTI- and NRTI-resistant HIV-1 isolates. Enzymatic studies indicated that these compounds are HIV-1 RT inhibitors. Surprisingly, however, following prolonged (6 months) tissue culture selection, this series of nonnucleoside inhibitors did not select NNRTI-resistant mutations in HIV-1 RT. Rather, four mutations (M41L, A62T/V, V118I, and M184V) known to cause resistance to NRTIs and two additional novel mutations (S68N and G112S) adjacent to the catalytic site of the enzyme were selected. Although the M184V mutation appears to be the initial mutation to establish resistance, this mutation alone confers only a two- to fourfold decrease in susceptibility to VRX-329747 and VRX-413638. At least two additional mutations must accumulate for significant resistance. Moreover, while VRX-329747-selected viruses are resistant to lamivudine and emtricitabine due to the M184V mutation, they remain susceptible to zidovudine, stavudine, dideoxyinosine, abacavir, tenofovir, and efavirenz. These results directly demonstrate that VRX-329747 and VRX-413638 are novel nonnucleoside inhibitors of HIV-1 RT with the potential to augment current therapies.

Sign in / Sign up

Export Citation Format

Share Document