Sarica Zehra, Kurkcuoglu Ozge, Sungur Fethiye Aylin
Computational Science and Engineering Division, Informatics Institute, Istanbul Technical University, Istanbul 34469, Türkiye.
Department of Chemical Engineering, Istanbul Technical University, Istanbul 34469, Türkiye.
Int J Mol Sci. 2025 Apr 2;26(7):3293. doi: 10.3390/ijms26073293.
RAS mutations occur in about 30% of human cancers, leading to enhanced RAS signaling and tumor growth. KRAS is the most commonly mutated oncogene in human tumors, especially lung, pancreatic, and colorectal cancers. Direct targeting of KRAS is difficult due to its highly conserved sequence; but, its complex with the guanine nucleotide exchange factor Son of Sevenless (SOS) 1 promises an attractive target for inhibiting RAS-mediated signaling. Here, we first revealed putative allosteric binding sites of the SOS1, KRASG12C-SOS1 complex, and the ternary KRASG13D-SOS1 complex structures using two network-based models, the essential site scanning analysis and the residue interaction network model. The results enabled us to identify two new putative allosteric pockets for the ternary KRASG13D-SOS1 complex. These were then screened together with the known ligand binding site against the natural compounds in the InterBioScreen (IBS) database using the Glide software package developed by Schrödinger, Inc. The docking poses of seven hit compounds were assessed using 400 ns long molecular dynamics (MD) simulations with two independent replicas using Desmond, coupled with thermal MM-GBSA calculations for the estimation of the binding free energy values. The structural skeleton of the seven proposed compounds consists of different functional groups and heterocyclic rings that possess anti-cancer activity and exhibit persistent interactions with key residues in binding pockets throughout the MD simulations. STOCK1N-09823 was determined as the most promising hit that promoted the disruption of the interactions R73 (chain A)/N879 and R73 (chain A)/Y884, which are key for SOS1-mediated KRAS activation.
RAS 突变发生在约 30% 的人类癌症中，导致 RAS 信号增强和肿瘤生长。KRAS 是人类肿瘤中最常发生突变的癌基因，尤其是在肺癌、胰腺癌和结直肠癌中。由于 KRAS 序列高度保守，直接靶向它很困难；但是，它与鸟嘌呤核苷酸交换因子七号less之子（SOS）1 的复合物有望成为抑制 RAS 介导信号传导的有吸引力的靶点。在这里，我们首先使用基于网络的两个模型，即必需位点扫描分析和残基相互作用网络模型，揭示了 SOS1、KRASG12C - SOS1 复合物以及三元 KRASG13D - SOS1 复合物结构的假定变构结合位点。结果使我们能够识别出三元 KRASG13D - SOS1 复合物的两个新的假定变构口袋。然后，使用 Schrödinger 公司开发的 Glide 软件包，将这些口袋与已知配体结合位点一起针对 InterBioScreen（IBS）数据库中的天然化合物进行筛选。使用 Desmond 进行两个独立复本的 400 纳秒长分子动力学（MD）模拟，并结合热 MM - GBSA 计算来评估七个命中化合物的对接姿势，以估计结合自由能值。这七种提议化合物的结构骨架由具有抗癌活性的不同官能团和杂环组成，并且在整个 MD 模拟过程中与结合口袋中的关键残基表现出持续的相互作用。STOCK1N - 09823 被确定为最有前景的命中化合物，它促进了 R73（链 A）/N879 和 R73（链 A）/Y884 相互作用的破坏，而这两个相互作用对于 SOS1 介导的 KRAS 激活至关重要。
