背景:K-Ras基因突变是各种癌症中最常见的遗传改变之一,和抑制RAS信号在治疗实体肿瘤方面显示出有希望的结果。然而,寻找能够与RAS蛋白结合的有效药物仍然具有挑战性。这促使我们探索可以抑制肿瘤生长的新化合物,特别是在有K-Ras突变的癌症中。
方法:我们的研究使用生物信息学技术,如电子药效团虚拟筛选,分子模拟,主成分分析(PCA),额外精度(XP)对接,和ADMET分析以鉴定K-Ras突变体G12C和G12D的潜在抑制剂。
结果:在我们的研究中,我们发现阿法替尼等抑制剂,奥希替尼,和羟氯喹强烈抑制G12C突变体。同样,羟嗪,zuclopenthixol,氟奋乃静,多沙普兰是G12D突变体的有效抑制剂。值得注意的是,所有6个这些分子对突变结构中存在的H95隐沟表现出高结合亲和力。这些分子在分子水平上表现出独特的亲和机制,疏水相互作用进一步增强。分子模拟和PCA揭示了在开关区I和II内形成稳定的复合物。这在三种复合物中尤为明显:G12C-奥希替尼,G12D-氟奋乃静,和G12D-zuclopenthixol。尽管K-Ras中的开关I和II具有动态性,抑制剂的相互作用保持稳定。根据QikProp的结果,与sotorasib相比,所选分子的性质和描述符落在可接受的范围内。
结论:我们已经成功鉴定了K-Ras蛋白的潜在抑制剂,为开发由K-Ras突变驱动的癌症靶向治疗奠定基础。
Mutations in the K-Ras gene are among the most frequent genetic alterations in various cancers, and inhibiting RAS signaling has shown promising results in treating solid tumors. However, finding effective drugs that can bind to the RAS protein remains challenging. This drove us to explore new compounds that could inhibit tumor growth, particularly in cancers that harbor K-Ras mutations.
Our study used bioinformatic techniques such as E-pharmacophore virtual screening, molecular simulation, principal component analysis (PCA), extra precision (XP) docking, and ADMET analyses to identify potential inhibitors for K-Ras mutants G12C and G12D.
In our study, we discovered that inhibitors such as afatinib, osimertinib, and hydroxychloroquine strongly inhibit the G12C mutant. Similarly, hydroxyzine, zuclopenthixol,
fluphenazine, and doxapram were potent inhibitors for the G12D mutant. Notably, all six of these molecules exhibit a high binding affinity for the H95 cryptic groove present in the mutant structure. These molecules exhibited a unique affinity mechanism at the molecular level, which was further enhanced by hydrophobic interactions. Molecular simulations and PCA revealed the formation of stable complexes within switch regions I and II. This was particularly evident in three complexes: G12C-osimertinib, G12D-
fluphenazine, and G12D-zuclopenthixol. Despite the dynamic nature of switches I and II in K-Ras, the interaction of inhibitors remained stable. According to QikProp results, the properties and descriptors of the selected molecules fell within an acceptable range compared to sotorasib.
We have successfully identified potential inhibitors of the K-Ras protein, laying the groundwork for the development of targeted therapies for cancers driven by K-Ras mutations.