Palafox M Alcolea
Chemical Physics Department, Chemistry Faculty, Complutense University, Ciudad Universitaria, Madrid-28040, Spain.
Phys Chem Chem Phys. 2014 Dec 7;16(45):24763-83. doi: 10.1039/c4cp03695f.
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.
对HIV-1逆转录酶抑制剂齐多夫定（3'-叠氮-3'-脱氧胸苷）核苷类似物的构象景观进行了全面的量子化学研究。分析了整个构象参数（χ、γ、β、δ、ϕ、P、νmax）以及自然键轨道（NBO）电荷。搜索定位了至少55个稳定结构，其中9个在全局最小值的1 kcal mol⁻¹电子能量范围内通过MP2方法得到。大多数构象异构体在糖苷键周围为反式或高反式，且糖环呈北式折叠角。根据特征扭转角的稳定性范围建立了所有构象异构体的分布。所得结果与相关抗HIV核苷类似物的结果一致。反式形式的最佳构象异构体对应于通过MP2计算得到的χ = -126.9°、β = 176.4°和γ = 49.1°的值。对构象异构体C1中的最低振动进行了分析。模拟了第一水合层，并确定了与天然核苷脱氧胸苷（dT）的结构差异。通过使ATP与齐多夫定和脱氧胸苷的最佳水合簇相互作用，模拟了第一步磷酸化过程。Na⁺阳离子作为ATP磷酸基团之间的桥梁，使得-P3O3易于从齐多夫定或脱氧胸苷接收H5'质子。提出了一种通过水分子的质子转移机制。当围绕齐多夫定的水分子数量低于8时，齐多夫定的第一步磷酸化过程可以进行。然而，脱氧胸苷中O5'-H的适当取向避免了这种限制，并且可以在大量水分子存在的情况下进行。
