Kumar Sachindra, Kumar B Harish, Nayak Raksha, Pandey Samyak, Kumar Nitesh, Pai K Sreedhara Ranganath
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, 576104, India.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hajipur, Vaishali, Bihar, 844102, India.
Mol Divers. 2025 Jan 9. doi: 10.1007/s11030-024-11075-5.
SH2 (Src Homology 2) domains play a crucial role in phosphotyrosine-mediated signaling and have emerged as promising drug targets, particularly in cancer therapy. STAT3 (Signal Transducer and Activator of Transcription 3), which contains an SH2 domain, plays a pivotal role in cancer progression and immune evasion because it facilitates the dimerization of STAT3, which is essential for their activation and subsequent nuclear translocation. SH2 domain-mediated STAT3 inhibition disrupts this binding, reduces phosphorylation of STAT3, and impairs dimerization. This study employed an in silico approach to screen potential natural compounds that could target the SH2 domain of STAT3 and inhibit its function. The phytomolecules (182455) were retrieved from the ZINC 15 database and were docked using various modes like HTVS, SP, and XP. The phytomolecules exhibiting higher binding affinity were selected. MM-GBSA was performed to determine binding free energy, and the QikProp tool was utilized to assess the pharmacokinetic properties of potential hit compounds, narrowing down the list of candidates. Molecular dynamics simulations, thermal MM-GBSA, and WaterMap analysis were performed on compounds that exhibited favorable binding affinities and pharmacokinetic characteristics. Based on docking scores and binding interactions, ZINC255200449, ZINC299817570, ZINC31167114, and ZINC67910988 were identified as potential STAT3 inhibitors. ZINC67910988 demonstrated superior stability in molecular dynamics simulation and WaterMap analysis. Furthermore, DFT was performed to determine energetic and electronic properties, and HOMO and LUMO sites were predicted for electronic structure calculation. Additionally, network pharmacology was performed to map the compounds' interactions within biological networks, highlighting their multitarget potential. Compound-target networks elucidate the relationships between compounds and multiple targets, along with their associated pathways and help to minimize off-target effects. The identified lead compound showed strong potential as a STAT3 inhibitor, warranting further validation through in vitro and in vivo studies.
SH2（Src同源2）结构域在磷酸酪氨酸介导的信号传导中起关键作用，并已成为有前景的药物靶点，尤其是在癌症治疗方面。STAT3（信号转导和转录激活因子3）含有一个SH2结构域，在癌症进展和免疫逃逸中起关键作用，因为它促进STAT3的二聚化，而这对其激活及随后的核转位至关重要。SH2结构域介导的STAT3抑制会破坏这种结合，减少STAT3的磷酸化，并损害二聚化。本研究采用计算机模拟方法筛选能够靶向STAT3的SH2结构域并抑制其功能的潜在天然化合物。从ZINC 15数据库中检索出植物分子（182455个），并使用HTVS、SP和XP等多种模式进行对接。选择具有更高结合亲和力的植物分子。进行MM - GBSA以确定结合自由能，并利用QikProp工具评估潜在命中化合物的药代动力学性质，从而缩小候选名单。对表现出良好结合亲和力和药代动力学特征的化合物进行分子动力学模拟、热MM - GBSA和WaterMap分析。基于对接分数和结合相互作用，确定ZINC255200449、ZINC299817570、ZINC31167114和ZINC67910988为潜在的STAT3抑制剂。ZINC67910988在分子动力学模拟和WaterMap分析中表现出卓越的稳定性。此外，进行密度泛函理论（DFT）以确定能量和电子性质，并预测最高占据分子轨道（HOMO）和最低未占据分子轨道（LUMO）位点用于电子结构计算。另外，进行网络药理学研究以绘制化合物在生物网络中的相互作用，突出其多靶点潜力。化合物 - 靶点网络阐明了化合物与多个靶点之间的关系及其相关途径，并有助于最小化脱靶效应。所鉴定的先导化合物显示出作为STAT3抑制剂的强大潜力，值得通过体外和体内研究进一步验证。
