PO.BCS01.05 · 生物信息与计算
GSK3alpha的计算机模拟分析以鉴定用于癌症治疗的新型潜在配体
In silico analysis of GSK3alpha to identify novel potential ligands for cancer therapy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
癌症仍是全球主要死亡原因。药物耐药和不良免疫事件等制约因素迫切需要为癌症患者寻找新的治疗靶点。糖原合成酶激酶3（GSK3）是一种多功能激酶，在癌症中具有情境依赖的双重作用。在GSK3的两个高度同源的哺乳动物异构体（即GSK3alpha和GSK3beta）中，我们探索了GSK3alpha的预测和预后作用以及新型潜在配体。使用TNM plot（https://tnmplot.com/analysis/）比较了正常组织和肿瘤组织中GSK3A基因的表达。使用Kaplan-Meier plotter（https://kmplot.com/analysis/）将GSK3A mRNA表达与接受免疫治疗的癌症患者的生存相关联，随访阈值为240个月，并采用中位表达量。使用ROC plotter（https://www.rocplot.com）分析GSK3A基因在接受免疫治疗的癌症患者中的预测作用。来自KM-和ROC-Plotter的数据使用Graphpad PRISM 8进行分析。计算了Logrank P值、95%置信区间和风险比（HR），P值<0.05被认为具有统计学显著性。使用PyRx Vina Wizard将来自Selleckchem化学数据库的五个配体库与GSK3alpha蛋白进行对接以用于虚拟筛选。具有良好结合能的配体使用ProTox 3.0（https://tox-new.charite.de/protox_II/）验证类药性。GSK3A基因表达在十二种肿瘤中显著高于正常组织，在两种正常组织中高于肿瘤组织。较高的GSK3A mRNA表达与接受免疫治疗患者更好的OS显著相关，而与PFS无关。ROC分析显示，GSK3A基因表达与抗PD-L1和抗CTLA-4联合治疗的应答显著相关，而与抗PD-1治疗无关。分子对接预测了几种与GSK3alpha具有强结合亲和力的配体。根据对接评分入选的药物被分析其类药性。MOLI001171、MOLI001205和甲酰甲呋喃（Formylmethanofuran）被发现是具有癌症治疗潜力的强效GSK3alpha配体。
查看英文原文 English abstract
Cancer prevails as the leading mortality cause worldwide. Constraints like drug resistance and adverse immune events urge the need to find novel treatment targets in cancer patients. Glycogen synthase kinase 3 (GSK3) is a multifunctional kinase that has context-dependent dual role in cancer. Out of the two highly homologous mammalian isoforms of GSK3 (i.e. GSK3alpha and GSK3beta), we explored the predictive and prognostic role, and novel potential ligands for GSK3alpha. GSK3A gene expression was compared in normal and tumor tissues using TNM plot ( https://tnmplot.com/analysis/ ). Kaplan-Meier plotter ( https://kmplot.com/analysis/ ) was used to correlate GSK3A mRNA expression with survival in cancer patients receiving immunotherapy, for a 240 months follow-up threshold and using median expression. ROC plotter (https://www.rocplot.com) was used to analyze the predictive role of GSK3A gene in cancer patients receiving immunotherapy. The data from KM- and ROC-Plotter was analyzed using Graphpad PRISM 8. Logrank P, 95% confidence intervals and Hazard ratio (HR) were calculated and P value of < 0.05 was considered to be statistically significant. Five ligand libraries from Selleckchem chemical database were docked with GSK3alpha protein using PyRx Vina Wizard for virtual screening. Ligands with favorable binding energies were validated for drug-likeliness using ProTox 3.0 ( https://tox-new.charite.de/protox_II/ ). GSK3A gene expression was significantly higher in twelve tumors than normal tissue and two normal than tumor tissue. Higher GSK3A mRNA expression was significantly correlated with better OS and not PFS in patients receiving immunotherapy. ROC analysis showed that GSK3A gene expression was significantly associated with combined response to anti-PD-L1 and anti-CTLA-4 therapy, and not to anti-PD-1 therapy. Molecular docking predicted several ligands with strong binding affinity to GSK3alpha. Shortlisted drugs based on their docking scores were analyzed for their drug-likeliness. MOLI001171, MOLI001205 and Formylmethanofuran were found to be potent GSK3alpha ligands with potential for cancer therapy.
利益披露 Disclosure
N. S. Walter, None..
S. Dora, None..
J. Kaur, None.