Ahmad Rumana
Department of Biochemisty, Era's Lucknow Medical College and Hospital, Era University, Lucknow, Uttar Pradesh, India.
PeerJ. 2019 Jan 3;7:e6012. doi: 10.7717/peerj.6012. eCollection 2019.
(black nightshade; ), a member of family Solanaceae, has been endowed with a heterogeneous array of secondary metabolites of which the steroidal glycoalkaloids (SGAs) and steroidal saponins (SS) have vast potential to serve as anticancer agents. Since there has been much controversy regarding safety of use of glycoalkaloids as anticancer agents, this area has remained more or less unexplored. Cytoskeletal proteins like actin play an important role in maintaining cell shape, synchronizing cell division, cell motility, etc. and along with their accessory proteins may also serve as important therapeutic targets for potential anticancer candidates. In the present study, glycoalkaloids and saponins from were screened for their interaction and binding affinity to cytoskeletal proteins, using molecular docking.
Bioactivity score and Prediction of Activity Spectra for Substances (PASS) analysis were performed using softwares Molinspiration and Osiris Data Explorer respectively, to assess the feasibility of selected phytoconstituents as potential drug candidates. The results were compared with two standard reference drugs doxorubicin hydrochloride (anticancer) and tetracycline (antibiotic). Multivariate data obtained were analyzed using principal component analysis (PCA).
Docking analysis revealed that the binding affinities of the phytoconstituents towards the target cytoskeletal proteins decreased in the order coronin>villin>ezrin>vimentin>gelsolin>thymosin>cofilin. Glycoalkaloid solasonine displayed the greatest binding affinity towards the target proteins followed by alpha-solanine whereas amongst the saponins, nigrumnin-I showed maximum binding affinity. PASS Analysis of the selected phytoconstituents revealed 1 to 3 violations of Lipinski's parameters indicating the need for modification of their structure-activity relationship (SAR) for improvement of their bioactivity and bioavailability. Glycoalkaloids and saponins all had bioactivity scores between -5.0 and 0.0 with respect to various receptor proteins and target enzymes. Solanidine, solasodine and solamargine had positive values of druglikeness which indicated that these compounds have the potential for development into future anticancer drugs. Toxicity potential evaluation revealed that glycoalkaloids and saponins had no toxicity, tumorigenicity or irritant effect(s). SAR analysis revealed that the number, type and location of sugar or the substitution of hydroxyl group on alkaloid backbone had an effect on the activity and that the presence of α-L-rhamnopyranose sugar at C-2 was critical for a compound to exhibit anticancer activity.
The present study revealed some cytoskeletal target(s) for phytoconstituents by docking analysis that have not been previously reported and thus warrant further investigations both and .
龙葵（茄科植物）富含多种次生代谢产物，其中甾体糖苷生物碱（SGAs）和甾体皂苷（SS）具有作为抗癌剂的巨大潜力。由于使用糖苷生物碱作为抗癌剂的安全性存在诸多争议，该领域或多或少仍未得到充分探索。像肌动蛋白这样的细胞骨架蛋白在维持细胞形状、同步细胞分裂、细胞运动等方面发挥着重要作用，并且与其辅助蛋白一起也可能成为潜在抗癌候选物的重要治疗靶点。在本研究中，利用分子对接技术筛选了龙葵中的糖苷生物碱和皂苷与细胞骨架蛋白的相互作用及结合亲和力。
分别使用软件Molinspiration和Osiris Data Explorer进行生物活性评分和物质活性谱预测（PASS）分析，以评估所选植物成分作为潜在药物候选物的可行性。将结果与两种标准参考药物盐酸多柔比星（抗癌药）和四环素（抗生素）进行比较。对获得的多变量数据使用主成分分析（PCA）进行分析。
对接分析表明，植物成分对目标细胞骨架蛋白的结合亲和力顺序为：冠蛋白＞绒毛蛋白＞埃兹蛋白＞波形蛋白＞凝溶胶蛋白＞胸腺素＞丝切蛋白。糖苷生物碱茄解碱对目标蛋白的结合亲和力最大，其次是α - 茄碱，而在皂苷中，黑茄皂苷 - I表现出最大的结合亲和力。对所选植物成分的PASS分析显示有1至3项违反了Lipinski参数，表明需要修改其构效关系（SAR）以提高其生物活性和生物利用度。糖苷生物碱和皂苷对各种受体蛋白和靶酶的生物活性评分均在 - 5.0至0.0之间。茄啶、茄解啶和茄玛碱的类药性质值为正，这表明这些化合物有开发成未来抗癌药物的潜力。毒性潜力评估表明，糖苷生物碱和皂苷没有毒性、致瘤性或刺激作用。SAR分析表明，糖的数量、类型和位置或生物碱骨架上羟基的取代对活性有影响，并且在C - 2位存在α - L - 鼠李糖对化合物表现出抗癌活性至关重要。
本研究通过对接分析揭示了一些龙葵植物成分的细胞骨架靶点，这些靶点此前尚未见报道，因此在体内和体外都值得进一步研究。
