Computational Screening of a Functional Cyclodextrin Derivative for Suppressing a Side Effect of Doxorubicin
Computational Screening of a Functional Cyclodextrin Derivative for Suppressing a Side Effect of Doxorubicin
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用于抑制阿霉素副作用的功能性环糊精衍生物的计算筛选
DOI：
10.1021/acs.jpcb.1c00373
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Hirata Fumio
中科院分区：
文献类型：
--
作者：
Sugita Masatake;Kuwano Izumi;Higashi Taishi;Motoyama Keiichi;Arima Hidetoshi;Hirata Fumio
为了筛选抑制抗癌药物副作用的化合物，采用3D-RISM/KH理论结合分子动力学模拟，研究了β-环糊精（β-CyD）衍生物与阿霉素（Dox）的结合亲和力。一个协议修订的外部和构象熵的主客体系统被用来计算结合自由能。结果发现，直接相互作用的CyD与Dox和两种化合物的去溶剂化自由能在很大程度上抵消离开适度的贡献的亲和力，这是可比的熵。结果揭示了熵项确定的结合亲和力，虽然外部熵项基本上是恒定的，在所有的化合物检查，并不影响筛选。将理论计算结果与实验数据进行了比较，其中一种CyD衍生物是通过不考虑熵项的初步计算预测的最佳化合物。
The binding affinity of the beta-cyclodextrin (β-CyD) derivatives with Doxorubicin (Dox) is evaluated by means of the 3D-RISM/KH theory combined with the molecular dynamics simulation in order to screen the compounds for suppressing a side-effect of the cancer drug. A protocol revised for the external and conformational entropies of the host–guest system is employed to calculate the binding free energy. It is found that the direct interactions of CyD with Dox and the desolvation free-energies of the both compounds largely cancel out to leave moderate contributions to the affinity, which are comparable to those from the entropies. The results shed light on the entropy terms for determining the binding affinity, although the external-entropy terms are essentially constant over all the compounds examined and do not affect the screening. The theoretical result is compared with the experimental data of the association constant for a CyD derivative which was predicted to be the best compound by the preliminary calculation without the entropy terms.