Correlation of anti-HIV activity with structure: use of electrostatic potential and conformational analysis

Mickle, Travis; Nair, Vasu

doi:10.1016/s0960-894x(99)00324-8

Cited by 9 publications

(6 citation statements)

References 12 publications

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“…This finding is supported by a computer modeling study comparing NRTIs in their lowest-energy state conformation. This study predicted that CBVTP would bind well to HIV-1 RT's active site (47). Our kinetic analysis showed that the primary effect of the carbocyclic ring of CBVTP was reflected in the maximum rate of incorporation (k pol ) into a homo-and heteroduplex, which was found to be reduced 23-24-fold relative to the rate of dGMP incorporation with RT WT .…”

Section: Discussionmentioning

confidence: 81%

Insights into the Molecular Mechanism of Inhibition and Drug Resistance for HIV-1 RT with Carbovir Triphosphate

et al. 2002

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Abacavir (1592U89, or Ziagen) is a powerful and selective inhibitor of HIV-1 viral replication that has been approved by the FDA for treatment of acquired immunodeficiency syndrome. Abacavir is metabolized to the active compound carbovir triphosphate (CBVTP). This compound is a guanosine analogue containing a 2',3'-unsaturation in its planar carbocyclic deoxyribose ring that acts on HIV-1 reverse transcriptase (RT(WT)) as a molecular target, resulting in chain termination of DNA synthesis. A single amino acid change from methionine 184 to valine in HIV-1 RT (RT(M184V)) has been observed clinically in response to abacavir treatment. The ability of the natural substrate, dGTP, or CBVTP to be utilized during DNA- and RNA-directed polymerization by RT(WT) and RT(M184V) was defined by pre-steady-state kinetic parameters. In the case of RT(WT), CBVTP was found to be a surprisingly poor substrate relative to dGTP. In both DNA- and RNA-directed polymerization, a decrease in the efficiency of CBVTP utilization with respect to dGTP was found with RT(M184V), suggesting that this mutation confers resistance at the level of CBVMP incorporation. The relatively low incorporation efficiency for RT(WT) was unanticipated considering earlier studies showing that the triphosphate form of a thymidine nucleoside analogue containing a planar 2',3'-unsaturated ribose ring, D4TTP, was incorporated with high efficiency relative to the natural substrate, dTTP. The difference may be related to the isosteric replacement of oxygen in the deoxyribose ring with carbon. This hypothesis was tested by synthesizing and evaluating D4GTP (the planar 2',3'-unsaturated deoxyribose guanosine analogue that is complementary to D4TTP). In contrast to CBVTP, D4GTP was found to be an excellent substrate for RT(WT) and no resistance was conferred by the M184V mutation, thus providing novel insight into structure-activity relationships for nucleoside-based inhibitors. In this work, we illustrate how an understanding of the molecular mechanism of inhibition and drug resistance led to the discovery of a novel prodrug of D4G. This compound shows promise as a potent antiviral especially with the drug resistant M184V HIV-1 RT that is so often encountered in a clinical setting.

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Section: Discussionmentioning

confidence: 81%

Insights into the Molecular Mechanism of Inhibition and Drug Resistance for HIV-1 RT with Carbovir Triphosphate

et al. 2002

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“…Area of high, neutral and low electrostatic potential is determined for boldine. The binding site in relevant enzyme is expected to have opposite areas of elec- trostatic potential [32]. From the ESP curve as shown in Fig.…”

Section: Molecular Electrostatic Potentialmentioning

confidence: 99%

Solid state characterization of an antioxidant alkaloid boldine using vibrational spectroscopy and quantum chemical calculations

Srivastava

Tandon

Ayala

et al. 2011

Vibrational Spectroscopy

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“…Both 3TC and FTC [(Ϫ)-␤-L-2Ј,3Ј-dideoxy-5-fluoro-3Ј-thiacytidine] show potent antiviral activity against HIV and hepatitis B virus, with favorable pharmacokinetic and toxicity profiles (20,43). Therefore, structural features and conformational preferences of the D and L enantiomers, as well as their interactions with the target enzymes, have been the critical issue to be studied (4,26,27,39,40,43).The activation of nucleoside RT inhibitors involves two major events: phosphorylation by kinases and the interaction of the deoxynucleoside triphosphate (dNTP) with the RT (14,30,35). The antiviral activity of 2Ј,3Ј-dideoxynucleosides is dependent on their phosphorylation by cellular kinases in the cytoplasm to the corresponding 5Ј-triphosphates.…”

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confidence: 99%

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confidence: 99%

Molecular Modeling Approach to Understanding the Mode of Action ofl-Nucleosides as Antiviral Agents

Lee

Chu

2001

Antimicrob Agents Chemother

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Antiretroviral therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infection has proven effective in extending the life and enhancing the quality of life of patients with AIDS (25). Thus far, six nucleoside reverse transcriptase (RT) inhibitors (NRTIs), four protease inhibitors, and three non-NRTIs have been approved by the Food and Drug Administration. In particular, NRTIs continue to be the mainstay of antiretroviral therapy (24, 31). For example, triple-combination therapy, consisting of zidovudine (AZT) (3Ј-azido-3Ј-deoxythymidine) (9,17,18,21,28) , 33, 34), and a protease inhibitor, is being used as the primary regimen for AIDS treatment (11,15). Therefore, a complete understanding of the mechanism of action of NRTIs at the molecular level continues to be an important scientific objective for design and development of more effective and less toxic agents.The NRTIs bear structural features common to 2Ј,3Ј-dideoxynucleosides, and the majority of the approved drugs have the natural D configurations: AZT, ddC (2Ј,3Ј-dideoxycytidine) (1, 5, 46), ddI (2Ј,3Ј-dideoxyinosine) (8, 12, 29, 47), d4T (2Ј,3Ј-didehydro-2Ј,3Ј-dideoxythymidine) (16,22), and abacavir (1592U89; succinate) (10, 38). Since the discovery of 3TC, however, a number of nucleosides with the unnatural L configuration have emerged as potent antiviral agents. Both 3TC and FTC [(Ϫ)-␤-L-2Ј,3Ј-dideoxy-5-fluoro-3Ј-thiacytidine] show potent antiviral activity against HIV and hepatitis B virus, with favorable pharmacokinetic and toxicity profiles (20,43). Therefore, structural features and conformational preferences of the D and L enantiomers, as well as their interactions with the target enzymes, have been the critical issue to be studied (4,26,27,39,40,43).The activation of nucleoside RT inhibitors involves two major events: phosphorylation by kinases and the interaction of the deoxynucleoside triphosphate (dNTP) with the RT (14,30,35). The antiviral activity of 2Ј,3Ј-dideoxynucleosides is dependent on their phosphorylation by cellular kinases in the cytoplasm to the corresponding 5Ј-triphosphates. These triphosphates compete with the corresponding endogenous nucleoside triphosphates at the catalytic site of the HIV-1 RT, and also, upon incorporation into the nascent DNA strand the nucleotides act as chain terminators of the DNA elongation. The initial phosphorylation of nucleosides requires several cellular kinases, such as thymidine kinase, deoxycytidine kinase, and adenosine kinase, and the activities of these kinases depend on the nature of the heterocyclic base as well as the structure and stereochemistry of the carbohydrate moiety (36).However, as three-dimensional structures of these kinases have not yet been determined, it is difficult to envision how the initial phosphorylation is carried out for unnatural nucleosides, such as L-nucleosides, without compromising the stereochemical requirements of the enzymes and/or the nucleosides. Furthermore, the active conformation of the 5Ј-triphosphates at the site of the RT is not well u...

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Correlation of anti-HIV activity with structure: use of electrostatic potential and conformational analysis

Cited by 9 publications

References 12 publications

Insights into the Molecular Mechanism of Inhibition and Drug Resistance for HIV-1 RT with Carbovir Triphosphate

Insights into the Molecular Mechanism of Inhibition and Drug Resistance for HIV-1 RT with Carbovir Triphosphate

Solid state characterization of an antioxidant alkaloid boldine using vibrational spectroscopy and quantum chemical calculations

Molecular Modeling Approach to Understanding the Mode of Action ofl-Nucleosides as Antiviral Agents

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