The model performance on the unseen dataset.

For cancer treatment, Inhibition of murine double minute (MDM2) & p53 interaction is considered an attractive therapeutic approach. In this study, we performed an integrated virtual screening (i.e., QSAR, structural similarity, molecular docking, and molecular dynamic simulation) on the in-house building alkaloids library. Geissolosimine (i.e., an indole alkaloid) was predicted as a potential inhibitor for MDM2-p53 interaction. The predicted pIC50 value of Geissolosimine, was 7.013 M. Moreover, Geissolosimine showed 0.62% structural similarity to ‘SAR405838’ (i.e., a clinical trial inhibitor for MDM2-p53 interaction inhibition); and a docking score of -10.9 kcal/mol that was higher than the ‘SAR405838’.100 ns molecular dynamics simulation (MDS) was performed to validate the docking result and it exhibited better binding stability to MDM2. The pharmacokinetic & drug-likeness analysis suggested that Geissolosimine had potential to be a drug-like compound. However, in vitro & in vivo assays will be required to validate this study.

在癌症治疗领域，靶向抑制鼠双微体（murine double minute, MDM2）与p53的相互作用被视为极具吸引力的治疗策略。本研究针对自建生物碱库开展了整合虚拟筛选工作，涵盖定量构效关系（Quantitative Structure-Activity Relationship, QSAR）、结构相似性分析、分子对接及分子动力学模拟等流程。研究预测，吲哚生物碱（indole alkaloid）类化合物盖西洛辛（Geissolosimine）可作为MDM2-p53相互作用的潜在抑制剂，其预测pIC50值为7.013 M。此外，盖西洛辛与MDM2-p53相互作用抑制剂的临床试验药物SAR405838的结构相似性仅为0.62%，但其分子对接得分达-10.9 kcal/mol，高于SAR405838。本研究通过100 ns分子动力学模拟（molecular dynamic simulation, MDS）验证了分子对接结果，结果显示盖西洛辛与MDM2的结合稳定性更优。药代动力学及成药性分析表明，盖西洛辛具备开发为类药化合物的潜力。不过，仍需开展体外及体内实验以验证本研究的预测结论。