和厚朴酚衍生物的设计、合成及分子对接研究
摘要
目的癌症是严重危害人类生命健康的重大疾病。随着对癌症发病机制的深入研究,众多与癌症相关的调节蛋白与抗癌靶标逐渐得到了阐明,促使抗癌药物从单纯的细胞毒药物向针对抗癌靶标的靶向药物发展。本研究拟从具有抗癌活性的中药单体和厚朴酚出发,通过反向分子对接的方法探讨其潜在的抗肿瘤作用靶点,为和厚朴酚的抗肿瘤分子机制提供一定的理论依据。在此基础上,围绕和厚朴酚潜在的作用靶点,设计并合成一系列衍生物,通过虚拟筛选的方法,寻找靶点选择性更高、活性更强的先导化合物。
方法本文以和厚朴酚为分子探针,选择了16个与抗肿瘤作用相关的靶标作为筛选对象,以结合自由能ΔG、抑制常数Ki作为筛选指标,在Autodock分子对接软件平台上进行反向分子对接研究；以和厚朴酚为先导化合物,基于基质金属蛋白酶MMP-2和MMP-9的结构,结合药物拼合原理,设计两系列和厚朴酚衍生物—通过不同的连接链,在和厚朴酚的4位羟基引入(5-卤代)尿嘧啶(系列Ⅰ)或N-1取代苄基(5-卤代)尿嘧啶结构片段(系列Ⅱ)。通过分子对接的方法,从设计的和厚朴酚衍生物中筛选出活性较高的化合物,并探讨这些衍生物的构效关系。通过Williamson反应、烃化反应等方法合成了9个虚拟活性较高的衍生物,目标化合物的结构通过1H NMR、MS等方法确证。
结果反向分子对接结果表明,和厚朴酚在环氧合酶-2(COX-2)、基质金属蛋白酶-9(MMP-9)、基质金属蛋白酶-2(MMP-2)、细胞周期蛋白依赖性激酶-2(CDK-2)和p38丝裂原活化蛋白激酶(p38 MAPK)中表现出较高的结合能力。其中,和厚朴酚与COX-2活性腔的结合能要高于原始配体—氟比洛芬。另外,和厚朴酚与MMP-2／9的对接模拟显示,和厚朴酚分子嵌入MMP-2／9活性腔的S1′口袋,这为我们提供较大的结构修饰空间。虚拟筛选结果表明,和厚朴酚系列Ⅱ衍生物与MMP-2／9的结合能高于系列Ⅰ衍生物,与活性腔的空间匹配较好。本文合成了系列Ⅱ衍生物中的9个化合物,结构经1H NMR、MS等方法确证,均未见文献报道。
结论环氧合酶-2(COX-2)、基质金属蛋白酶-2／9(MMP-2／9)、细胞周期蛋白依赖性激酶2(CDK-2)和p38丝裂原活化蛋白激酶(p38 MAPK)均有可能是和厚朴酚发挥抗肿瘤作用的潜在结合靶标。和厚朴酚4位羟基连接取代苄基尿嘧啶结构片段有利于提高与MMP-2／9活性腔的结合能力。
Objective Cancer is a severe disease threatening the health and lives of human being. Current treatments of cancer have limited effectiveness and numerous serious unintended side effects. Following advances on the pathogenetic mechanisms of cancer, more and more regulatory protein and drug targets relating cancer have been clarified, promoting the development of anticancer drugs from cytotoxic drugs to targeted drugs. The Chinese medicine have afforded a rich source of anticancer agents with multi-targeted and low toxicity. Hence, our study focused on the active component isolated from Chinese traditional herb magnolia—honokiol with potential anticancer activities. To understand the antitumor mechanisms of honokiol at molecule level, we investigate the potential antitumor targets of honokiol with reverse docking approach. To increase the activity of honokiol, we designed and synthesized a serial of honokiol analogues based on the existing SAR study of honokiol and virtual screening method.
Methods The reverse docking study was performed on the autodock4.2 program, honokiol was used as a probe,16 antitumor targets were selected as screen objects, binding energyΔG and inhibition constant Ki were used to evaluate the docking results. Based on the structures of matrix metalloproteinases 2/9, as well as the combination principle, two serials of honokiol derivatives were designed. Virtual screening method with autodock4.2 program was used to evaluate the activities of the designed analogues. All of the three dimensional structures of compounds prepared for docking study were constructed by the Corina program. Nine honokiol analogues were synthesized by Williamson reaction and alkylation reaction, the structures of which were confirmed by 1H NMR, MS.
Results Reverse docking results revealed that the binding energy between honokiol and COX-2, MMP-9, MMP-2, CDK-2 and p38 MAPK are ranked at the top of the list, in which the binding energy between honokiol and COX-2 is higher than the positive control compound—flurbiprofen. In addition, molecule modeling showed that honokiol inserted into the S1' pocket of MMP2/9, and leave space for structural modification. Virtual screening results showed that the series II of honokiol derivatives possessed higher affinity than the series I analogues, as well as space match, with MMP-9. Nine honokiol derivatives of series II have been synthesized, all of which have not been reported in literature.
Conclusions COX-2, MMP-9, MMP-2, CDK-2 and p38 MAPK are the potential binding targets of honokiol. The structure of N1-substituted benzyl-(5-halogeno) uracil at 4-position of hydroxyl group of honokiol plays important role in the affinity between honokiol derivatives of seriesⅡand MMP2/9.
方法本文以和厚朴酚为分子探针,选择了16个与抗肿瘤作用相关的靶标作为筛选对象,以结合自由能ΔG、抑制常数Ki作为筛选指标,在Autodock分子对接软件平台上进行反向分子对接研究；以和厚朴酚为先导化合物,基于基质金属蛋白酶MMP-2和MMP-9的结构,结合药物拼合原理,设计两系列和厚朴酚衍生物—通过不同的连接链,在和厚朴酚的4位羟基引入(5-卤代)尿嘧啶(系列Ⅰ)或N-1取代苄基(5-卤代)尿嘧啶结构片段(系列Ⅱ)。通过分子对接的方法,从设计的和厚朴酚衍生物中筛选出活性较高的化合物,并探讨这些衍生物的构效关系。通过Williamson反应、烃化反应等方法合成了9个虚拟活性较高的衍生物,目标化合物的结构通过1H NMR、MS等方法确证。
结果反向分子对接结果表明,和厚朴酚在环氧合酶-2(COX-2)、基质金属蛋白酶-9(MMP-9)、基质金属蛋白酶-2(MMP-2)、细胞周期蛋白依赖性激酶-2(CDK-2)和p38丝裂原活化蛋白激酶(p38 MAPK)中表现出较高的结合能力。其中,和厚朴酚与COX-2活性腔的结合能要高于原始配体—氟比洛芬。另外,和厚朴酚与MMP-2／9的对接模拟显示,和厚朴酚分子嵌入MMP-2／9活性腔的S1′口袋,这为我们提供较大的结构修饰空间。虚拟筛选结果表明,和厚朴酚系列Ⅱ衍生物与MMP-2／9的结合能高于系列Ⅰ衍生物,与活性腔的空间匹配较好。本文合成了系列Ⅱ衍生物中的9个化合物,结构经1H NMR、MS等方法确证,均未见文献报道。
结论环氧合酶-2(COX-2)、基质金属蛋白酶-2／9(MMP-2／9)、细胞周期蛋白依赖性激酶2(CDK-2)和p38丝裂原活化蛋白激酶(p38 MAPK)均有可能是和厚朴酚发挥抗肿瘤作用的潜在结合靶标。和厚朴酚4位羟基连接取代苄基尿嘧啶结构片段有利于提高与MMP-2／9活性腔的结合能力。
Objective Cancer is a severe disease threatening the health and lives of human being. Current treatments of cancer have limited effectiveness and numerous serious unintended side effects. Following advances on the pathogenetic mechanisms of cancer, more and more regulatory protein and drug targets relating cancer have been clarified, promoting the development of anticancer drugs from cytotoxic drugs to targeted drugs. The Chinese medicine have afforded a rich source of anticancer agents with multi-targeted and low toxicity. Hence, our study focused on the active component isolated from Chinese traditional herb magnolia—honokiol with potential anticancer activities. To understand the antitumor mechanisms of honokiol at molecule level, we investigate the potential antitumor targets of honokiol with reverse docking approach. To increase the activity of honokiol, we designed and synthesized a serial of honokiol analogues based on the existing SAR study of honokiol and virtual screening method.
Methods The reverse docking study was performed on the autodock4.2 program, honokiol was used as a probe,16 antitumor targets were selected as screen objects, binding energyΔG and inhibition constant Ki were used to evaluate the docking results. Based on the structures of matrix metalloproteinases 2/9, as well as the combination principle, two serials of honokiol derivatives were designed. Virtual screening method with autodock4.2 program was used to evaluate the activities of the designed analogues. All of the three dimensional structures of compounds prepared for docking study were constructed by the Corina program. Nine honokiol analogues were synthesized by Williamson reaction and alkylation reaction, the structures of which were confirmed by 1H NMR, MS.
Results Reverse docking results revealed that the binding energy between honokiol and COX-2, MMP-9, MMP-2, CDK-2 and p38 MAPK are ranked at the top of the list, in which the binding energy between honokiol and COX-2 is higher than the positive control compound—flurbiprofen. In addition, molecule modeling showed that honokiol inserted into the S1' pocket of MMP2/9, and leave space for structural modification. Virtual screening results showed that the series II of honokiol derivatives possessed higher affinity than the series I analogues, as well as space match, with MMP-9. Nine honokiol derivatives of series II have been synthesized, all of which have not been reported in literature.
Conclusions COX-2, MMP-9, MMP-2, CDK-2 and p38 MAPK are the potential binding targets of honokiol. The structure of N1-substituted benzyl-(5-halogeno) uracil at 4-position of hydroxyl group of honokiol plays important role in the affinity between honokiol derivatives of seriesⅡand MMP2/9.
引文
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