Uncovering the molecular and physiological processes of anticancer leads binding human serum albumin: A physical insight into drug efficacy.
Uncovering the molecular and physiological processes of anticancer leads binding human serum albumin: A physical insight into drug efficacy.
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揭示抗癌先导物结合人血清白蛋白的分子和生理过程：药物功效的物理洞察
DOI：
10.1371/journal.pone.0176208
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Liu C;Liu Z;Wang J
人血清白蛋白（HSA）具有结合药物分子并影响其功效的能力。抗癌先导化合物NSC48693和NSC290956虽然作用机制相同，但药效明显不同。为了深入了解独特的药物功效，通过实验和理论相结合的方法研究了抗癌先导化合物结合 HSA 的分子和生理过程。通过荧光猝灭和分子建模表征，发现结合位点分别位于具有紧密结合的 NSC48693 子结构域 III A 中的位点 II 和具有负协同结合的 NSC290956 子结构域 I B 中的位点 FA1。热力学分析表明，NSC48693通过焓驱动机制与HSA结合，而NSC290956与HSA结合是熵驱动机制。进一步的动力学分析表明，关联率似乎与这两种抗癌先导化合物相似，然而，NSC48693 的解离率比 NSC290956 慢约 5 倍。对于NSC48693，其药效学功效低于NSC290956，而其药代动力学行为优于NSC290956。这些参数影响药效功效和药代动力学行为，从而进一步影响药物在体内的功效。
Human serum albumin (HSA) has its ability to bind drug molecules and influence their efficacies. Although anticancer leads NSC48693 and NSC290956 functioned at the same mechanism, the drug efficacies were obviously distinct. To gain insight into the distinct drug efficacy, the molecular and physiological processes of anticancer leads binding HSA have been investigated via a combined experimental and theoretical approach. The binding site, as characterized by fluorescence quenching and molecular modeling, is found to be located at site II in subdomain III A for NSC48693 with tight binding and at site FA1 in subdomain I B for NSC290956 with negatively cooperative binding, respectively. As indicated by the thermodynamic analysis, NSC48693 binds to HSA with an enthalpy driven mechanism, while NSC290956 binding with HSA is entropically driven. The further kinetic analysis indicates that the association rates appear to be similar to these two anticancer leads, however, the dissociation rate of NSC48693 is approximately 5-fold slower than that of NSC290956. For NSC48693, the pharmacodynamic efficacy is less than that of NSC290956, while its pharmacokinetic behavior is better than that of NSC290956. These parameters influence the pharmacodynamic efficacy and pharmacokinetic behavior, which will give further impacts on drug efficacy in vivo.