In 2014, two novel and promising benzimidazole-based APOBEC3G stabilizers MM-1 and MM-2 (MMs) were uncovered with an elusive mechanism of action. Vif-APOBEC3G axis has been recognized as a novel therapeutic target for anti HIV-1 drug development. The unexplored mechanism of MMs hindered their further development into lead compounds. To recognize their underlying mechanism we adopted an exhaustive in silico workflow by which we tested their ability to interrupt Vif complex network formation. The preliminary outcome guided us to a high likelihood of MMs interaction within Elongin C binding site, which in turn, perturbs Vif/Elongin C binding and ultimately undermines Vif action. To validate our estimation, we synthesized only MM-1 as a model to complement our study by in vitro assay for a real-time understanding. An immunoprecipitation experiment confirmed the capacity of MM-1 to interrupt Vif/Elongin C interaction. This is an integral study that lies at the interface between theoretical and experimental approaches showing the potential of molecular modelling to address issues related to drug development.

2014年，发现了两种新颖且很有前景的基于苯并咪唑的APOBEC3G稳定剂MM-1和MM-2（MMs），其作用机理难以捉摸。Vif-APOBEC3G轴已被公认为是抗HIV-1药物开发的新型治疗靶标。MM的尚未探索的机制阻碍了它们进一步发展为铅化合物。为了认识他们的潜在机制，我们采用了详尽的计算机软件工作流程，通过该工作流程，我们测试了他们中断Vif复杂网络形成的能力。初步结果指导我们发生MM的可能性很高Elongin C结合位点内的相互作用，反过来扰乱Vif / Elongin C结合并最终破坏Vif的作用。为了验证我们的估计，我们仅合成了MM-1作为模型，以通过体外测定对我们的研究进行补充，以实现实时了解。免疫沉淀实验证实了MM-1中断Vif / Elongin C相互作用的能力。这是一项不可或缺的研究，位于理论方法与实验方法之间的接口上，显示了分子建模解决与药物开发有关的问题的潜力。