Department of Biochemistry, Universidade Federal do Ceará, Fortaleza 60455-760, Ceará, Brazil.
J Phys Chem B. 2012 Mar 15;116(10):3270-9. doi: 10.1021/jp206397z. Epub 2012 Mar 6.
The resulting noncovalent bonding of the salicylic acid to ovine COX-1 after bromoaspirin and aspirin acetylation by Ser530 is investigated within the scope of density functional theory considering a 6.5 Å radius binding pocket. We have not only took full advantage of published X-ray structural data for the ovine COX-1 cocrystallized with bromoaspirin, but we also have improved that data through computation, finding good estimates for the hydrogen atom positions at the residues of the binding pocket, and repositioning the Ser530Ac[Br;H] lateral chain and salicylic acid by total energy minimization procedures employing LDA and GGA+D exchange-correlation functionals. Using bromoaspirin as a template, we have simulated the positioning of aspirin in the binding pocket, estimating its interaction energy with each of its neighbor COX-1 residues. We demonstrate that the binding energies of bromoaspirin and aspirin to COX-1 are very close when second-order quantum refinements of the structural data are performed, which points to an explanation on why the IC(50) values for the 126 μM COX-1 activity of both bromoaspirin and aspirin are practically the same. Attracting and repelling residues were identified, being shown that Arg120 is the most effective residue attracting the salicylic acid, followed by Ala527, Leu531, Leu359, and Ser353. On the other hand, Glu524 was found the most effective repulsive residue (strength interaction comparable to Arg120).
在考虑 6.5 Å 半径结合口袋的范围内，通过 Ser530 对溴水合醋柳酸和阿司匹林进行乙酰化，研究了水杨酸与绵羊 COX-1 的非共价键结合。我们不仅充分利用了发表的绵羊 COX-1 与溴水合醋柳酸共晶的 X 射线结构数据，而且还通过计算对该数据进行了改进，找到了结合口袋残基处氢原子位置的良好估计值，并通过使用 LDA 和 GGA+D 交换相关泛函的总能量最小化程序，重新定位 Ser530Ac[Br;H]侧链和水杨酸。我们以溴水合醋柳酸为模板，模拟了阿司匹林在结合口袋中的定位，估计了它与每个相邻 COX-1 残基的相互作用能。我们证明，当对结构数据进行二阶量子细化时，溴水合醋柳酸和阿司匹林与 COX-1 的结合能非常接近，这解释了为什么溴水合醋柳酸和阿司匹林对 126 μM COX-1 活性的 IC（50）值几乎相同。鉴定了吸引和排斥残基，结果表明 Arg120 是吸引水杨酸的最有效残基，其次是 Ala527、Leu531、Leu359 和 Ser353。另一方面，发现 Glu524 是最有效的排斥残基（相互作用强度可与 Arg120 相媲美）。
