Selected Features.

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潜力的治疗策略。本研究针对自研生物碱文库开展了整合虚拟筛选，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（Molecular Dynamics Simulation, MDS）四大技术手段。吉索洛西明（Geissolosimine，一种吲哚类生物碱）被预测为MDM2-p53相互作用的潜在抑制剂，其预测pIC50值为7.013 M。此外，吉索洛西明与SAR405838的结构相似性仅为0.62%，而SAR405838是一款处于临床试验阶段的MDM2-p53相互作用抑制剂；同时吉索洛西明的对接得分为-10.9 kcal/mol，高于SAR405838。本研究通过100纳秒（ns）分子动力学模拟对对接结果进行验证，结果显示吉索洛西明与MDM2的结合稳定性更优。药代动力学与成药性分析表明，吉索洛西明具备成为类药化合物的潜力。不过，该研究结论仍需通过体外及体内实验予以验证。