AZT and related compounds—a theoretical study

Ciuffo, Gladys M.; Santillan, M.B.; Estrada, Mario R.; Yamı́n, Lázaro J.; Jáuregui, Esteban A.

doi:10.1016/s0166-1280(97)00273-x

Cited by 13 publications

(19 citation statements)

References 15 publications

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“…For instance, efficient phosphorylation depends largely on the spatial structure of the nucleoside, specially the O5 0 H orientation. 5,8,18,[37][38][39][40] The current manuscript completes our extensive investigation of the conformational families of the 2 0 ,3 0 -didehydro-2 0 ,3 0 -dideoxy analogues of the canonical nucleosides. For this reason, the conformers of natural nucleosides and nucleoside analogues have been analyzed by different authors.…”

Section: Introductionmentioning

confidence: 79%

“…Several earlier studies at the low computational level have been devoted to the conformational analysis of AZT, mainly at PCILO 37a,f and at AM1 8,14,30,40 semiempirical levels. Several earlier studies at the low computational level have been devoted to the conformational analysis of AZT, mainly at PCILO 37a,f and at AM1 8,14,30,40 semiempirical levels.…”

Section: Resultsmentioning

confidence: 99%

“…(8) The effects of the Na cations on the ATP structure were considered. Several possible binding of ATP with AZT were analyzed.…”

Section: Discussionmentioning

confidence: 99%

“…8 In 1987 the Food and Drug Administration (FDA) 9 approved the first antiretroviral therapy with AZT in the infections caused by the Human Immunodeficiency Virus (HIV). 8 In 1987 the Food and Drug Administration (FDA) 9 approved the first antiretroviral therapy with AZT in the infections caused by the Human Immunodeficiency Virus (HIV).…”

Section: Introductionmentioning

confidence: 99%

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Structure and conformational analysis of the anti-HIV reverse transcriptase inhibitor AZT using MP2 and DFT methods. Differences with the natural nucleoside thymidine. Simulation of the 1st phosphorylation step with ATP

Palafox

2014

Phys. Chem. Chem. Phys.

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A comprehensive quantum-chemical investigation of the conformational landscape of the HIV-1 reverse transcriptase inhibitor AZT (3'-azido-3'-deoxythymidine) nucleoside analogue was carried out. The whole conformational parameters (χ, γ, β, δ, ϕ, P, νmax) were analysed as well as the NBO charges. The search located at least 55 stable structures, 9 of which were by MP2 within a 1 kcal mol(-1) electronic energy range of the global minimum. Most conformers were anti or high-anti around the glycoside bond and with North sugar ring puckering angles. The distribution of all the conformers according to the ranges of stability of the characteristic torsional angles was established. The results obtained were in accordance with those found in related anti-HIV nucleoside analogues. The best conformer in the anti form corresponded to the calculated values by MP2 of χ = -126.9°, β = 176.4° and γ = 49.1°. An analysis of the lowest vibrations in conformer C1 was carried out. The first hydration shell was simulated and the structural differences with the natural nucleoside deoxythymidine (dT) were determined. The first phosphorylation step was simulated by interacting ATP with the best hydrated clusters of AZT and dT. The Na cations act as a bridge between the phosphate moieties of ATP making it easy for -P3O3 to receive the H5' proton from AZT or dT. A proton-transfer mechanism is proposed through the water molecules. When the number of the water molecules surrounding AZT is lower than 8, the first phosphorylation step of AZT can be carried out. However, the appropriate orientation of the O5'-H in dT avoids this limitation and it can be performed with large numbers of water molecules.

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Section: Introductionmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 99%

“…(8) The effects of the Na cations on the ATP structure were considered. Several possible binding of ATP with AZT were analyzed.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structure and conformational analysis of the anti-HIV reverse transcriptase inhibitor AZT using MP2 and DFT methods. Differences with the natural nucleoside thymidine. Simulation of the 1st phosphorylation step with ATP

Palafox

2014

Phys. Chem. Chem. Phys.

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“…However, molecular recognition studies with the phosphorylating kinases are complicated by the fact that the crystal structures of some of these enzymes have not been determined. However, examination of electrostatic potential surfaces (EPS) has suggested that if molecules have similar electrostatic potentials, along with some other key properties such as conformation, hydrophobicity, and hydrogen-bonding sites, then it is more probable that their molecular recognition by enzymes and receptors would be similar (2,8,28,33). Thus, by using electrostatic potential, fundamental structural properties can be examined for qualitative and quantitative correlations.…”

mentioning

confidence: 99%

Anti-Human Immunodeficiency Virus Activities of Nucleosides and Nucleotides: Correlation with Molecular Electrostatic Potential Data

Mickle

Nair

2000

Antimicrob Agents Chemother

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Investigation of nucleoside analogs with anti‐HIV activity

Arissawa

Taft

Felcman

2003

Int J of Quantum Chemistry

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ABSTRACT:Although a relatively large number of drugs that inhibit human immunodeficiency syndrome (HIV)-1 reverse transcriptase have been developed-such as AZT, d4T, ddI, 3TC, and ddC, which are chain terminating nucleoside analogs-resistance is still a major problem. Atomic charges, regioselective patterns of chemical reactivity, and other indices of biochemical activity may help us acquire a better understanding of how the drugs work and the mechanism of drug resistance. In this work, we investigated the above-mentioned nucleoside analogs using the ab initio Hartree-Fock method with 3-21G, 3-21G*, 6-31G, 6-31G*, 6-31G**, and 6-31ϩG** basis sets as well as B3LYP/6-31G**, including thus diffusion, polarization, and correlation effects to obtain fully optimized geometric parameters. Vibrational frequencies were calculated and we also investigated the effects of solvents, Mulliken, and natural bond orbital charge distribution, as well as hydrogen bond effects. We tried to correlate very low and very high anti-HIV activity with charges, vibrational stretching frequencies, interatomic distances, and the effect of solvents.

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AZT and related compounds—a theoretical study

Cited by 13 publications

References 15 publications

Structure and conformational analysis of the anti-HIV reverse transcriptase inhibitor AZT using MP2 and DFT methods. Differences with the natural nucleoside thymidine. Simulation of the 1st phosphorylation step with ATP

Structure and conformational analysis of the anti-HIV reverse transcriptase inhibitor AZT using MP2 and DFT methods. Differences with the natural nucleoside thymidine. Simulation of the 1st phosphorylation step with ATP

Anti-Human Immunodeficiency Virus Activities of Nucleosides and Nucleotides: Correlation with Molecular Electrostatic Potential Data

Investigation of nucleoside analogs with anti‐HIV activity

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