Metabolic & Structural Biology Department, Plant Biology Division, CSIR-Central Institute of Medicinal & Aromatic Plants (CIMAP), P.O.-CIMAP, Kukrail Picnic Spot Road, Lucknow-226015 (Uttar Pradesh). India.
Medicinal Chemistry Department, CSIR-Central Institute of Medicinal & Aromatic Plants (CIMAP), P.O.-CIMAP, Kukrail Picnic Spot Road, Lucknow-226015 (Uttar Pradesh). India.
Curr Cancer Drug Targets. 2017;17(8):722-734. doi: 10.2174/1568009617666170330152617.
Natural products showed anticancer activity and often induce apoptosis or autophagy in cancer cells through the PI3K/Akt/mTOR signaling pathways. The potential of natural products as PI3Ks inhibitors has been reported, which suggest PI3Ks a promising anticancer target. Phosphoinositide 3-kinase is a family of related intracellular signal transducer enzymes or lipid kinases that regulate different cellular processes involved in cancer.
To identify the molecular reason behind the similar target based activity of selected shikimate pathway metabolites on PI3Kγ, a detail structure-activity relationship study was performed.
In the studied work, anticancer potential of plant molecules gallic acid and serpentine was evaluated against PI3Kγ isoform and compared with wortmannin, a steroid metabolite of the fungi and a non-specific covalent known inhibitor of PI3Ks by using in-silico QSAR, docking, ADMET, chemical isolation from plant, NMR and in-vitro activity.
A predictive QSAR model was developed by applying multiple linear regression which revealed identification of key structural properties regulating the inhibitory activity of serpentine and gallic acid on PI3Kγ. The model exhibited acceptable statistical parameters such as r2 0.76, r2CV 0.72, and q2 0.55. Structural elucidation was done through NMR studies. Predicted activities were further evaluated through in-vitro testing of gallic acid and serpentine targeting PI3Kγ.
The identified chemical features modulating the activity were amide, amine, and secondary amine groups counts, highest occupied molecule orbital (HOMO) energy and valence connectivity index (order 2). In-silico ADME and toxicity risk assessment was done for pharmacokinetic and bioavailability compliance evaluation.
天然产物具有抗癌活性，通常通过 PI3K/Akt/mTOR 信号通路在癌细胞中诱导细胞凋亡或自噬。已经报道了天然产物作为 PI3Ks 抑制剂的潜力，这表明 PI3Ks 是一种有前途的抗癌靶标。磷酸肌醇 3-激酶是一个相关的细胞内信号转导酶或脂质激酶家族，调节涉及癌症的不同细胞过程。
为了确定选定的莽草酸途径代谢物对 PI3Kγ 具有相似靶标活性的分子原因，进行了详细的构效关系研究。
在研究工作中，评估了植物分子没食子酸和蛇根草对 PI3Kγ 同工型的抗癌潜力，并与真菌甾体代谢物渥曼青霉素进行了比较，渥曼青霉素是一种非特异性共价 PI3Ks 已知抑制剂，采用计算机 QSAR、对接、ADMET、从植物中化学分离、NMR 和体外活性进行比较。
通过应用多元线性回归建立了一个预测 QSAR 模型，该模型揭示了调节蛇根草和没食子酸对 PI3Kγ 抑制活性的关键结构特性的识别。该模型表现出可接受的统计参数，如 r2 0.76、r2CV 0.72 和 q2 0.55。通过 NMR 研究进行结构阐明。通过体外测试没食子酸和蛇根草针对 PI3Kγ 的活性进一步评估了预测活性。
确定了调节活性的化学特征是酰胺、胺和仲胺基团计数、最高占据分子轨道（HOMO）能量和价连接指数（顺序 2）。进行了计算机 ADME 和毒性风险评估，以评估药代动力学和生物利用度的合规性。
