用分子模拟方法研究HIV-1整合酶与咖啡酰基类抑制剂的相互作用

用分子对接和分子动力学(MD)模拟方法研究了一类咖啡酰基和没食子酰基类HIV-1整合酶抑制剂与整合酶之间的相互作用模式, 结果表明该类抑制剂分子上的两个侧链基团(咖啡酰基或没食子酰基)与整合酶的DDE基序之间的相互作用对抑制整合酶活性起到关键作用. 当侧链基团为没食子酰基时, 可以提高该类抑制剂与整合酶的结合能力. 采用线性相互作用能方法(LIE)计算了该类抑制剂与整合酶之间的结合自由能, 预测值与实验值相吻合, 均方根偏差RMSD为1.39 kJ•mol^-1, 以上结果可为基于结构的HIV-1整合酶抑制剂设计提供有用的信息.     

A concise synthesis of HIV integrase inhibitors bearing the dipyridone acid motif

An efficient route to dipyridone acid HIV integrase inhibitors is developed. The key steps include a one-pot three-step formation of the core template (containing one point of structural diversity) followed by a regioselective benzylation and in situ deprotection to afford the title compounds.     

The synthesis of tetrahydropyridopyrimidones as a new scaffold for HIV-1 integrase inhibitors

An efficient synthesis of methyl 9-amino-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate as a late stage intermediate for a new class of HIV-1 integrase inhibitors is described. After construction of the bicyclic core scaffold, a stereoselective introduction of the chiral amino group in the 9-position is achieved.     

Synthesis of cinnamate ester–AZT conjugates as potential dual-action HIV-1 integrase and reverse transcriptase inhibitors

Synthetic approaches to a series of novel cinnamate ester–AZT conjugates have been explored and a successful pathway has finally been developed. α-(Halomethyl)cinnamate esters, obtained in high yield by treating benzyl-protected salicylaldehde-derived Baylis–Hillman adducts with acetyl bromide at low temperature, have been treated with propargylamine to afford substrates for click chemistry reactions with azidothymidine (AZT) in the presence of in situ generated Cu(I) catalyst to produce the title compounds.     

人类免疫缺陷病毒整合酶二酮酸类抑制剂的三维药效团构建

应用遗传算法相似性程序(GASP), 以作用于I型人类免疫缺陷病毒(human immun-odeficiency virus type 1, HIV-1)整合酶(IN)的二酮酸类(diketoacids, DKAs)抑制剂构建药效团模型. 所选训练集分子均具有可靠的类药性特征及DKAs药效团特征. 尝试将抑制剂与药效团叠合后的构象和抑制剂与IN的对接构象进行叠合, 得到药效团模型与分子对接构象中IN残基的相对位置, 并基于抑制剂的药效团模型特征与周围IN氨基酸残基位置的匹配情况进行药效团特征的修改. 所得最优药效团由1个疏水特征、3对氢键特征和1个氢键供体特征组成. 该药效团的命中物质量(goodness of hit, GH)为0.56, 产出率(Y)达63.6%, 假阳性率(FP)为0.41%. 该药效团具有较好的置信度, 产出率较高而假阳性率较低, 可用于数据库搜索发现新的具有DKAs药效团特征的活性化合物, 也可为先导化合物的改造提供帮助.     

Synthesis of 6-sulfamoyl-4-oxoquinoline-3-carboxylic acid derivatives as integrase antagonists with anti-HIV activity

A series of novel 6-sulfamoyl-4-oxoquinoline-3-carboxylic acids derivatives have been synthesized and screened for HIV integrase inhibition activity.Their structures were confirmed by ESI-MS,~1H NMR and ~(13)C NMR.     

An accurate and precise high-performance liquid chromatography method for the rapid quantification of the novel HIV integrase inhibitor raltegravir in human blood plasma after solid phase extraction

The quantification of the HIV integrase inhibitor raltegravir in blood plasma is described using solid phase extraction (SPE) coupled with an accurate high-performance liquid chromatography assay with ultraviolet (UV) detection. The method was validated over the range of 20-10,000 ng/mL using simple sample preparation and chromatography. The SPE method was optimized to be selective and highly efficient. The buffer’s ionic strength and pH were optimized for retaining RAL and the internal standard on the column, the percentage of methanol was optimized in the cleaning step to remove unwanted plasma contaminants, and the type and amount of acid was optimized for complete elution of the compounds. This method has no interference with other potentially co-administered antiretrovirals or common drugs. Average recoveries for the extraction method were consistently high: 90% for raltegravir and 90% for the internal standard diazepam. This method was found to be accurate and precise. Within day (n = 6) and between day (n = 18) accuracies ranged from 97.5 to 104.4%. Within-day (n = 6) and between-day (n = 18) precision ranged from 1.4 to 3.8%, and from 2.4 to 7.9%, respectively. This is the first published method to use simple UV technology and reliable SPE extraction methodology for the quantification of raltegravir in human plasma. This method can be easily implemented in most bioanalytical laboratories.     

HIV-1病毒DNA与整合酶结合后的构象变化

用分子动力学(MD)模拟方法优化了HIV-1病毒DNA与整合酶(IN)二聚体(IN2)复合物模型结构, 并分析了HIV-1病毒DNA结合IN2后的构象变化. 结果表明, 按照HIV-1病毒DNA与IN2结合能力的强度, 病毒DNA可分为五个区域: 非结合区、强结合区1、弱结合区、强结合区2和反应区, 并用结合自由能计算验证了该分区的合理性. 与未结合IN2的病毒DNA相比, 复合物模型中病毒DNA除了非结合区碱基外, 其它四个区域的碱基构象变化较大. 复合物模型中病毒DNA主链较大程度地偏离标准B型DNA以及结合部位的小沟变宽都是识别IN的结构基础. 模拟结果与实验数据吻合较好, 为基于HIV-1 IN的药物分子设计提供了一定的结构信息.