基于结构的虚拟筛选和分子模拟研究，旨在使用已获FDA批准的药物作为双重癌症免疫治疗以抑制人体内HDAC6和VISTA。
Structure based virtual screening and molecular simulation study of FDA-approved drugs to inhibit human HDAC6 and VISTA as dual cancer immunotherapy.
发表日期：2023 Sep 02
作者：
Muhammad Shahab, Haitham Al-Madhagi, Guojun Zheng, Amir Zeb, Abdullah Fayez Alasmari, Metab Alharbi, Fawaz Alasmari, Muhammad Qayash Khan, Momin Khan, Abdul Wadood
来源：
PHARMACOLOGY & THERAPEUTICS
摘要：
免疫癌症治疗对于治疗各种类型的癌症具有显著贡献，主要通过靶向免疫检查点抑制剂（ICI）。其中，V-区域免疫球蛋白抑制T细胞激活（VISTA）已被探索作为一个有前途的治疗靶点。此外，组蛋白去乙酰化酶6（HDAC6）已被证明是多种癌症的有效靶点。本研究旨在探索FDA批准的药物在抑制VISTA和HDAC6这两个癌症治疗靶点上的虚拟再用途。两种蛋白的晶体结构从PDB下载后，通过DrugRep网络服务器进行虚拟筛选，使用FDA批准的药物库作为配体数据库。我们的研究发现，奥沙酮和倍沙托平分别是VISTA和HDAC6的排名靠前的抑制剂。倍沙托平的对接评分预测为-10 kcal/mol，奥沙酮的对接评分预测为-6.2 kcal/mol。此外，总计100 ns的分子动力学模拟显示，奥沙酮和倍沙托平两种药物与VISTA和HDAC6的靶点形成了稳定的复合物。与标准药物相比，奥沙酮和倍沙托平两种药物在整个100 ns的分子动力学模拟过程中表现出较好的稳定性。结合自由结合能计算进一步支持了平均均方差(RMSD)结果，表明相对于ref/HDAC6(- 18.0253 ± 2.6218)，倍沙托平/HDAC6的结合自由能评分良好(- 51.9698 ± 3.1572 kcal/mol)。奥沙酮/VISTA和ref/VISTA的结合自由能评分分别计算为- 36.8323 ± 3.4565和- 21.5611 ± 4.8581。总之，这两种药物值得进一步考虑作为癌症治疗选择。© 2023. Springer Nature Limited.
Cancer immunotherapy has significantly contributed to the treatment of various types of cancers mainly by targeting immune checkpoint inhibitors (ICI). Among them, V-domain immunoglobulin suppressor of T cell activation (VISTA) has been explored as a promising therapeutic target. Besides, histone deacetylase 6 (HDAC6) has been demonstrated to be efficacious target for several cancers. The current theoretical work was performed to explore the virtual repurposing of the FDA-approved drugs as inhibitors against these two (VISTA and HDAC6) cancers therapeutic targets. The crystal structure of the two proteins were downloaded from PDB and subjected to virtual screening by DrugRep webserver while using FDA-approved drugs library as ligands database. Our study revealed that Oxymorphone and Bexarotene are the top-ranked inhibitors of VISTA and HDAC6, respectively. The docking score of Bexarotene was predicted as - 10 kcal/mol while the docking score of Oxymorphone was predicted as - 6.2 kcal/mol. Furthermore, a total of 100 ns MD simulation revealed that the two drugs Oxymorphone and Bexarotene formed stable complexes with VISTA and HDAC6 drug targets. As compared to the standard drug the two drugs Oxymorphone and Bexarotene revealed great stability during the whole 100 ns MD simulation. The binding free energy calculation further supported the Root Mean Square Deviation (RMSD) result which stated that as compared to the ref/HDAC6 (- 18.0253 ± 2.6218) the binding free energy score of the Bexarotene/HDAC6 was good (- 51.9698 ± 3.1572 kcal/mol). The binding free energy score of Oxymorphone/VISTA and Ref/VISTA were calculated as - 36.8323 ± 3.4565, and - 21.5611 ± 4.8581 respectively. In conclusion, the two drugs deserve further consideration as cancer treatment option.© 2023. Springer Nature Limited.