Department of Chemistry, University of South Florida , 4202 E. Fowler Avenue, CHE205, Tampa, Florida 33620-5250, United States.
J Chem Inf Model. 2013 Nov 25;53(11):2951-61. doi: 10.1021/ci400395c. Epub 2013 Oct 28.
Hydroxyurea (HU) is the only FDA approved medication for treating sickle cell disease in adults. The primary mechanism of action is pharmacological elevation of nitric oxide (NO) levels which induces propagation of fetal hemoglobin. HU is known to undergo redox reactions with heme based enzymes like hemoglobin and catalase to produce NO. However, specific details about the HU based NO release remain unknown. Experimental studies indicate that interaction of HU with human catalase compound I produces NO. Presently, we combine flexible receptor-flexible substrate induced fit docking (IFD) with energy decomposition analyses to examine the atomic level details of a possible key step in the clinical conversion of HU to NO. Substrate binding modes of nine HU analogs with catalase compound I were investigated to determine the essential properties necessary for effective NO release. Three major binding orientations were found that provide insight into the possible reaction mechanisms for producing NO. Further results show that anion/radical intermediates produced as part of these mechanisms would be stabilized by hydrogen bonding interactions from distal residues His75, Asn148, Gln168, and oxoferryl-heme. These details will ideally contribute to both a clearer mechanistic picture and provide insights for future structure based drug design efforts.
羟基脲 (HU) 是唯一被 FDA 批准用于治疗成人镰状细胞病的药物。其主要作用机制是药理学上提高一氧化氮 (NO) 水平，从而诱导胎儿血红蛋白的增殖。已知 HU 与血红素基酶（如血红蛋白和过氧化氢酶）发生氧化还原反应，产生 NO。然而，HU 产生 NO 的具体机制仍不清楚。实验研究表明，HU 与人过氧化氢酶复合物 I 相互作用会产生 NO。目前，我们将柔性受体-柔性底物诱导契合对接 (IFD) 与能量分解分析相结合，以检查 HU 向 NO 临床转化的一个可能关键步骤的原子水平细节。研究了九种 HU 类似物与过氧化氢酶复合物 I 的底物结合模式，以确定有效释放 NO 所需的必要特性。发现了三种主要的结合方向，为产生 NO 的可能反应机制提供了深入了解。进一步的结果表明，作为这些机制一部分产生的阴离子/自由基中间体将通过来自远端残基 His75、Asn148、Gln168 和氧合血红素的氢键相互作用得到稳定。这些细节将有助于更清晰地了解其作用机制，并为未来基于结构的药物设计工作提供见解。
