AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom.
J Chem Inf Model. 2011 May 23;51(5):1048-63. doi: 10.1021/ci2000506. Epub 2011 May 4.
It has been known for a long time that certain substructures bind to the heme iron in cytochromes P450. Detection of spectroscopic changes and crystal structures of protein ligand complexes have provided qualitative evidence, including for aromatic nitrogen-containing ligands. Compounds containing these same substructures are more likely to inhibit cytochrome P450s than expected due to lipophilicity. These two sets of observations are not easily linked by experiment, because binding to the iron atom alone is not readily measured. Quantum mechanical (density functional) calculations of binding energies for a number of different aromatic heterocycles to heme iron in a range of oxidation and spin states can provide a quantitative link between the observed structures and the biochemical inhibition that is measured. The studies reported here for a set of heteroaromatic rings containing nitrogen begin with quantum mechanical calculations which provide geometries and binding energies. Subsequently, AstraZeneca's database of cytochrome P450 inhibition assays has been searched to find data that are relevant to the same set of heteroaromatic compounds. These data have been analyzed in a number of fashions to account for both the narrow dynamic range of the assays and the lipophilicity dependence of this kind of inhibition. Finally, crystal structures have provided experimental geometric information. Taken together these different sources suggest that binding to the metal in our inhibition assays is dominated by Fe(III) in its doublet state, most likely occurring when the iron is pentavalent. Computed binding energies to this state contrast with the hydrogen-bond acceptor ability and basicity of the compounds, neither of which are able to correctly account for the effect of the particular environment in which the iron is found. This highlights the value of modeling biochemical events as closely as can be computationally afforded. The computational protocol devised was used to make predictions about a set of as yet unknown heteroaromatic compounds suggested by Pitt et al.
长期以来，人们已经知道某些亚结构与细胞色素 P450 中的血红素铁结合。光谱变化的检测和蛋白质配体复合物的晶体结构提供了定性证据，包括芳香含氮配体。由于亲脂性，包含这些相同亚结构的化合物更有可能抑制细胞色素 P450 ，而不是预期的那样。由于仅结合到铁原子本身不易测量，这两组观察结果不易通过实验进行链接。对一系列不同的芳香杂环与血红素铁在一系列氧化和自旋状态下的结合能进行量子力学（密度泛函）计算，可以在观察到的结构与所测量的生化抑制之间提供定量联系。本文报道的一组含氮杂芳环的研究始于量子力学计算，该计算提供了几何形状和结合能。随后，阿斯利康的细胞色素 P450 抑制测定数据库被搜索，以找到与同一组杂芳族化合物相关的数据。这些数据以多种方式进行了分析，以解释测定的窄动态范围和这种抑制的亲脂性依赖性。最后，晶体结构提供了实验几何信息。这些不同的来源表明，在我们的抑制测定中与金属的结合主要由其双重态的 Fe(III)主导，最有可能发生在铁为五价时。计算出的与该状态的结合能与化合物的氢键接受能力和碱性形成对比，这两者都不能正确解释铁所处的特定环境的影响。这突出了尽可能密切地模拟生化事件的价值。设计的计算方案用于对 Pitt 等人提出的一组未知的杂芳族化合物进行预测。
