The anaphase-promoting complex/cyclosome (APC/c) is requisite for controlling mitosis, which is activated by Cdh1 and Cdc20 activators. Dysregulation of APC/c is observed in many cancers and is known as a targeted drug particularly in cancer drug resistance. It was shown that tosyl-l-arginine methyl ester (TAME), via mimicking isoleucine-arginine (IR) tail of co-activators, inhibits APC/c functions. However, structure details and interaction of TAME with APC/c are poorly defined. In the current study, a well-established set of computational methods was used to identify the best binding pocket in order to inhibit APC activity. Therefore, the interaction of IR tail and Cbox of co-activators, as well as TAME as an inhibitor, as an inhibitor, with APC3 and APC8 subunits of APC/c were analyzed, regarding structure, molecular docking, molecular dynamics, and free binding energy. The results indicated that TAME bound to APC3 with a higher binding affinity (∼−7.3 kcal/mol) than APC8 (∼−5.7 kcal/mol). Also, the binding free energy value obtained for the APC3-TAME was −22.25 ± 1.12 kcal/mol. According to binding free energies, van der Waals energy was the major favorable contributor to the ligand binding. These results offer that TAME had more affinity to interact with the APC3 subunit, at the IR binding pocket than the APC8 subunit at the Cbox binding pocket. In conclusion, IR binding pocket can serve as an appropriate potential target for TAME as an inhibitor of APC/c.

后期促进复合物/环体（APC / c）是控制有丝分裂的必要条件，该有丝分裂由Cdh1和Cdc20激活剂激活。在许多癌症中都观察到APC / c的失调，并且被称为靶向药物，尤其是在癌症耐药性方面。结果表明，甲苯磺酰升-精氨酸甲酯（TAME）通过模仿辅助活化剂的异亮氨酸-精氨酸（IR）尾部抑制APC / c功能。但是，TAME与APC / c的结构细节和相互作用尚不明确。在当前的研究中，一套完善的计算方法被用来确定最佳的结合口袋以抑制APC活性。因此，分析了IR尾巴和共激活剂Cbox以及TAME作为抑制剂与APC / c的APC3和APC8亚基的相互作用，涉及结构，分子对接，分子动力学和自由结合能源。结果表明，TAME以比APC8（〜-5.7 kcal / mol）更高的结合亲和力（〜-7.3 kcal / mol）与APC3结合。另外，对于APC3-TAME获得的结合自由能值为-22.25±1.12kcal / mol。根据结合的自由能，范德华能量是配体结合的主要有利因素。这些结果提供了，TAME在IR结合口袋处比在Cbox结合口袋处与APC8亚单位具有更多的亲和力与APC3亚单位相互作用。总之，IR结合口袋可作为AAME / c抑制剂的TAME合适的潜在靶标。