Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia.
Oncol Res. 2023 Dec 28;32(2):251-259. doi: 10.32604/or.2023.043139. eCollection 2023.
Gastric cancers are caused primarily due to the activation and amplification of the EGFR or HER2 kinases resulting in cell proliferation, adhesion, angiogenesis, and metastasis. Conventional therapies are ineffective due to the intra-tumoral heterogeneity and concomitant genetic mutations. Hence, dual inhibition strategies are recommended to increase potency and reduce cytotoxicity. In this study, we have conducted computational high-throughput screening of the ChemBridge library followed by assays and identified novel selective inhibitors that have a dual impediment of EGFR/HER2 kinase activities. Diversity-based High-throughput Virtual Screening (D-HTVS) was used to screen the whole ChemBridge small molecular library against EGFR and HER2. The atomistic molecular dynamic simulation was conducted to understand the dynamics and stability of the protein-ligand complexes. EGFR/HER2 kinase enzymes, KATOIII, and Snu-5 cells were used for validations. The atomistic Molecular Dynamics simulations followed by solvent-based Gibbs binding free energy calculation of top molecules, identified compound C3 (5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl) phenyl]-1H-isoindole-1,3(2H)-dione) to have a good affinity for both EGFR and HER2. The predicted compound, C3, was promising with better binding energy, good binding pose, and optimum interactions with the EGFR and HER2 residues. C3 inhibited EGFR and HER2 kinases with IC values of 37.24 and 45.83 nM, respectively. The GI values of C3 to inhibit KATOIII and Snu-5 cells were 84.76 and 48.26 nM, respectively. Based on these findings, we conclude that the identified compound C3 showed a conceivable dual inhibitory activity on EGFR/HER2 kinase, and therefore can be considered as a plausible lead-like molecule for treating gastric cancers with minimal side effects, though testing in higher models with pharmacokinetic approach is required.
胃癌主要是由于 EGFR 或 HER2 激酶的激活和扩增导致细胞增殖、黏附、血管生成和转移引起的。由于肿瘤内异质性和伴随的基因突变，传统疗法无效。因此，建议采用双重抑制策略来提高效力和降低细胞毒性。在这项研究中，我们对 ChemBridge 文库进行了计算高通量筛选，然后进行了 测定，确定了新型选择性抑制剂，它们对 EGFR/HER2 激酶活性具有双重抑制作用。基于多样性的高通量虚拟筛选 (D-HTVS) 用于筛选 ChemBridge 小分子文库对 EGFR 和 HER2 的抑制作用。进行了原子分子动力学模拟以了解蛋白-配体复合物的动力学和稳定性。使用 EGFR/HER2 激酶酶、KATOIII 和 Snu-5 细胞进行验证。原子分子动力学模拟后，对 top 分子进行基于溶剂的 Gibbs 结合自由能计算，确定化合物 C3（5-(4-氧代-4H-3,1-苯并恶嗪-2-基)-2-[3-(4-氧代-4H-3,1-苯并恶嗪-2-基)苯基]-1H-异吲哚-1,3(2H)-二酮）对 EGFR 和 HER2 具有良好的亲和力。预测的化合物 C3 具有更好的结合能、良好的结合构象和与 EGFR 和 HER2 残基的最佳相互作用，因此很有前途。C3 对 EGFR 和 HER2 激酶的抑制 IC 值分别为 37.24 和 45.83 nM。C3 抑制 KATOIII 和 Snu-5 细胞的 GI 值分别为 84.76 和 48.26 nM。基于这些发现，我们得出结论，鉴定的化合物 C3 对 EGFR/HER2 激酶表现出可想象的双重抑制活性，因此可以被认为是一种治疗胃癌的潜在类似物，具有最小的副作用，尽管需要通过药代动力学方法在更高的模型中进行测试。
