Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, British Columbia V6H 3Z6, Canada.
J Chem Inf Model. 2020 Aug 24;60(8):3703-3721. doi: 10.1021/acs.jcim.0c00325. Epub 2020 Aug 3.
Topoisomerase II (TopoII) is an enzyme essential for cellular metabolism and replication as it regulates DNA topology. Since inhibition of TopoII induces cell death, it is a well-established drug target in cancer therapy; several broadly used anticancer drugs including etoposide and doxorubicin are TopoII inhibitors. However, these therapeutics tend to cause severe side effects and suffer from relatively low ligand affinity, leaving TopoII targeting with small molecules an active area of research. In recent years computer-aided drug discovery (CADD) approaches have been actively used to expand knowledge on the role of TopoII in cancer and to develop novel strategies for its inhibition. Herein, we overview studies that employed structure-based approaches such as docking and molecular dynamic simulations, as well as ligand-based approaches, such as QSAR (quantitative structure-activity relationship) modeling among others, to gain understanding in TopoII targeting with existing drugs and to search for novel drug candidates.
拓扑异构酶 II（TopoII）是一种对细胞代谢和复制至关重要的酶，因为它调节 DNA 拓扑结构。由于抑制 TopoII 会诱导细胞死亡，因此它是癌症治疗中一种成熟的药物靶点；几种广泛使用的抗癌药物，包括依托泊苷和阿霉素，都是 TopoII 抑制剂。然而，这些治疗方法往往会导致严重的副作用，并且配体亲和力相对较低，因此小分子靶向 TopoII 仍然是一个活跃的研究领域。近年来，计算机辅助药物发现（CADD）方法被积极用于扩展对 TopoII 在癌症中的作用的认识，并开发其抑制的新策略。在此，我们综述了使用基于结构的方法（如对接和分子动力学模拟）以及基于配体的方法（如定量构效关系（QSAR）建模等）的研究，以深入了解现有药物对 TopoII 的靶向作用，并寻找新的候选药物。
