Alzain Abdulrahim A, Almogaddam Mohammed A, Makki Alaa A, Edris Alaa, Mohamed Hagar M, Ehaimir Sitelbanat Y, Mohamed Shaimaa G A, Taher Felemban Sarah Ameen, Hammad Alshammari Wedad Hamad, Mohamed Gamal A, Ibrahim Sabrin R M
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Wad Madani, Sudan.
Department of Medical Laboratory Analysis, Faculty of Medical and Health Sciences, Liwa University, Abu Dhabi, United Arab of Emirates.
J Pharm Bioallied Sci. 2025 Jun;17(Suppl 2):S1894-S1899. doi: 10.4103/jpbs.jpbs_534_25. Epub 2025 Jun 18.
The son of sevenless (SOS) proteins are rat sarcoma virus nucleotide exchange factors that act as regulatory switches of the rat sarcoma virus (RAS) system through the conversion of the inactive guanosine diphosphate (GDP) bound RAS to the GTP-bound active form, thereby modulating numerous biological events. SOSs contribute in disease incidence and progression in numerous cancers. Currently, SOSs inhibiting strategies deemed a substantial interest in the fight against cancer.
To date, there are various SOS1 inhibitors in the clinical trials, however there are no reported SOS2 inhibitors so far. In this study, we explored the Enamine fragments library against SOS2 through the multidisciplinary computational analysis. Pharmacophore modelling based on the previously published SOS2 inhibitory fragments has shed light on the influential pharmacophoric features. Subsequently, molecular docking and molecular mechanics/generalized born surface area (MM-GBSA) calculations rescored these findings, while molecular dynamics (MD) simulation examined the durability of SOS2-ligand intersections.
As a result, three Enamine fragments (Z284596, Z501753, and Z481369) postulated superior docking scores and binding free energies than the crystalized reference bound to SOS2 protein.
Furthermore, they postulated a reasonable MD profile. Overall, this study suggested three potential hit fragments with SOS2 inhibitory activity and can be experimentally verified.
七号缺失蛋白（SOS）家族是大鼠肉瘤病毒核苷酸交换因子，通过将与鸟苷二磷酸（GDP）结合的无活性RAS转化为与鸟苷三磷酸（GTP）结合的活性形式，充当大鼠肉瘤病毒（RAS）系统的调节开关，从而调节众多生物学事件。SOS在多种癌症的发病和进展中发挥作用。目前，SOS抑制策略在抗癌斗争中备受关注。
迄今为止，有多种SOS1抑制剂正处于临床试验阶段，但目前尚无SOS2抑制剂的报道。在本研究中，我们通过多学科计算分析，对Enamine片段文库进行了针对SOS2的研究。基于先前发表的SOS2抑制片段进行的药效团建模揭示了有影响的药效团特征。随后，分子对接和分子力学/广义玻恩表面积（MM-GBSA）计算对这些结果进行了重新评估，而分子动力学（MD）模拟则检验了SOS2-配体相互作用的稳定性。
结果显示，三个Enamine片段（Z284596、Z501753和Z481369）的对接分数和结合自由能优于与SOS2蛋白结合的结晶参考物。
此外，它们呈现出合理的分子动力学特征。总体而言，本研究提出了三个具有SOS2抑制活性的潜在命中片段，可进行实验验证。
