Department of Chemistry, Mashhad Branch, Islamic Azad University, Mashhad, IR Iran.
Iran J Basic Med Sci. 2013 Jun;16(6):784-9.
OBJECTIVE(S): Recently we reported that the soybean 15-lipoxygenase (SLO) inhibitory activity of pyrimido[4,5-b][l,4]benzothiazines largely depends on the orientation of sulfur atom of thiazine core towards Fe(III)-OH in the active site pocket of the enzyme with subsequent oxidation of sulfur to sulfoxide. In this paper the results of a comparative study on the SLO inhibitory activities of the mentioned compounds using ab initio calculations and docking analyses has been reported.
Structure optimization and docking analyses were performed using HyperChem 7.5 and AutoDock Tools 4.0 respectively. Enzyme assessment was reduced using spectrophotometric MBTH-DMAB method. Results : The inhibitory activity of synthetic 2-substituted pyrimido[4,5-b][l,4]benzothiazines against soybean 15-lipoxygenase (SLO) was evaluated and structure activity relationships and binding modes of their 4-H and 4-methyl analogs were studied using docking analysis and ab initio calculations.
The results of these studies showed that the lack of 4-methyl substituent in the pyrimido[4,5-b][1,4]benzothiazine molecules greatly reduces their lipoxygenase inhibitory activities and it was also found that the HOMO energy difference between the 4-H and 4-Methyl analogs can be responsible for the observed inhibitory activity reduction.
Our molecular modeling studies shows that by using more flexible amino acids during the docking process, more rational results can be obtained. The method of measuring the lipoxygenase activity is also of prime importance for the study of structure activity relationship.
目的（Objective）：最近，我们报道了大豆 15-脂氧合酶（SLO）抑制活性的嘧啶并[4,5-b][1,4]苯并噻嗪类化合物在很大程度上取决于噻嗪核的硫原子在酶活性位点口袋中朝向 Fe（III）-OH 的方向，随后硫原子被氧化为亚砜。本文报道了使用从头算计算和对接分析对所述化合物的 SLO 抑制活性进行比较研究的结果。
材料和方法（Materials and Methods）：结构优化和对接分析分别使用 HyperChem 7.5 和 AutoDock Tools 4.0 进行。酶评估使用分光光度法 MBTH-DMAB 法进行。结果：评估了合成的 2-取代嘧啶并[4,5-b][1,4]苯并噻嗪对大豆 15-脂氧合酶（SLO）的抑制活性，并通过对接分析和从头算计算研究了其 4-H 和 4-甲基类似物的构效关系和结合模式。
讨论（Discussion）：这些研究的结果表明，嘧啶并[4,5-b][1,4]苯并噻嗪分子中缺乏 4-甲基取代基会大大降低其脂氧合酶抑制活性，并且还发现 4-H 和 4-甲基类似物之间的 HOMO 能量差可能是导致观察到的抑制活性降低的原因。
结论（Conclusion）：我们的分子建模研究表明，通过在对接过程中使用更灵活的氨基酸，可以获得更合理的结果。测量脂氧合酶活性的方法对于研究构效关系也非常重要。
