Discovery of Mcl-1 inhibitors through virtual screening, molecular dynamics simulations and in vitro experiments
Discovery of Mcl-1 inhibitors through virtual screening, molecular dynamics simulations and in vitro experiments
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通过虚拟筛选、分子动力学模拟和体外实验发现 Mcl-1 抑制剂
DOI：
10.1016/j.compbiomed.2022.106350
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发表时间：
2022-11
影响因子：
7.7
通讯作者：
Zhonghua Liu
中科院分区：
文献类型：
--
作者：
Ji;a Yue;Yaqi Li;Fengjiao Li;Peng Zhang;Yimin Li;Jiawei Xu;Qianqian Zhang;Cheng Zhang;Xiao He;Ying Wang;Zhonghua Liu
髓系白血病细胞分化蛋白（Mcl-1）作为B细胞淋巴瘤2（Bcl-2）蛋白家族的一员，能够抑制细胞凋亡，在肿瘤逃逸细胞凋亡的过程中发挥积极作用。因此，抑制Mcl-1蛋白可以有效促进肿瘤细胞的凋亡，也可能降低肿瘤细胞对针对其他抗凋亡蛋白的药物的耐药性。本研究致力于Mcl-1抑制剂的开发，旨在为不同支架的先导化合物为靶向抗癌药物的开发提供更多参考。我们通过Specs数据库的分子对接获得了一系列具有共同核心骨架的小分子，并在ZINC数据库中搜索核心结构以寻找更多相似的小分子。收集这些小分子进行初步实验筛选，我们发现了一批活性化合物，并筛选出对B16F10细胞抑制活性最强的两个小分子：化合物7和化合物1。它们的IC50分别为7.86±1.25和24.72±1.94μM。这两种化合物也被用于 B16F10 细胞的细胞划痕测试和其他细胞系的细胞活力测定。此外，通过分子动力学（MD）模拟分析，我们发现化合物7与Mcl-1的关键P2、P3口袋和ARG 263形成了强结合。最后，ADME结果显示化合物7在药物相似性方面表现良好。总之，这项研究提供了联合支架的成果，可能有助于设计针对 Mcl-1 的有效临床药物和未来的药物开发。
As a member of the B-cell lymphoma 2 (Bcl-2) protein family, the myeloid leukemia cell differentiation protein (Mcl-1) can inhibit apoptosis and plays an active role in the process of tumor escape from apoptosis. Therefore, inhibition of Mcl-1 protein can effectively promote the apoptosis of tumor cells and may also reduce tumor cell resistance to drugs targeting other anti-apoptotic proteins. This research is dedicated to the development of Mcl-1 inhibitors, aiming to provide more references for lead compounds with different scaffolds for the development of targeted anticancer drugs. We obtained a series of small molecules with a common core skeleton through molecular docking from Specs database and searched the core structure in ZINC database for more similar small molecules. Collecting these small molecules for preliminary experimental screening, we found a batch of active compounds, and selected two small molecules with the strongest inhibitory activity on B16F10 cells: compound 7 and compound 1. Their IC50s are 7.86 ± 1.25 and 24.72 ± 1.94 μM, respectively. These two compounds were also put into cell scratch test for B16F10 cells and cell viability assay of other cell lines. Furthermore, through molecular dynamics (MD) simulation analysis, we found that compound 7 formed strong binding with the key P2, P3 pocket and ARG 263 of Mcl-1. Finally, ADME results showed that compound 7 performs well in terms of drug similarity. In conclusion, this study provides hits with co-scaffolds that may aid in the design of effective clinical drugs targeting Mcl-1 and the future drug development.
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影响因子：
28.2
作者：
Ramsey HE;Fischer MA;Lee T;Gorska AE;Arrate MP;Fuller L;Boyd KL;Strickland SA;Sensintaffar J;Hogdal LJ;Ayers GD;Olejniczak ET;Fesik SW;Savona MR
通讯作者：
Savona MR
手性如何决定组蛋白脱乙酰酶 6 的选择性抑制？
影响因子：
5
作者：
Zhang Yang;Ying Jun Biao;Hong Jia Jun;Li Feng Chen;Fu Ting Ting;Yang Feng Yuan;Zheng Guo Xun;Yao Xiao Jun;Lou Yan;Qiu Yunqing;Xue Wei Wei;Zhu Feng
通讯作者：
Zhu Feng
影响因子：
10.1
作者：
Carter BZ;Mak PY;Tao W;Warmoes M;Lorenzi PL;Mak D;Ruvolo V;Tan L;Cidado J;Drew L;Andreeff M
通讯作者：
Andreeff M
影响因子：
--
作者：
Lasica M;Anderson MA
通讯作者：
Anderson MA
影响因子：
3.5
作者：
Rizzi, Andrea;Jensen, Travis;Chodera, John D.
通讯作者：
Chodera, John D.