Kirsten大鼠肉瘤2型病毒致癌基因同源物（KRAS）作为分子开关，在鸟苷三磷酸（GTP）结合和无活性的鸟苷二磷酸（GDP）结合状态之间循环。KRAS调节诸多信号转导途径，包括传统的RAF-MEK-ERK途径。RAS基因的突变已被证实与恶性肿瘤形成相关。人类恶性肿瘤通常表现出Ras基因突变，包括HRAS、KRAS和NRAS。在KRAS基因外显子12和外显子13的所有突变中，G12D突变在胰腺和肺癌中更为普遍，占所有G12突变的约41％，从而使它们成为潜在的抗癌治疗靶点。本研究旨在重新利用KRAS G12D突变体的肽抑制剂KD2。我们采用计算突变的方法，从实验报告的肽抑制剂中设计新的肽抑制剂，发现置换（N8W、N8I和N8Y）可能增强肽对KRAS的结合亲和力。分子动力学模拟和结合能量计算证实，新设计的肽抑制剂是稳定的，它们的结合亲和力强于野生型肽。详细分析表明，新设计的肽具有抑制KRAS/Raf相互作用和KRAS G12D突变体致癌信号的潜力。我们的研究结果强烈建议对这些肽进行测试和临床验证，以对抗KRAS的致癌活动。由Ramaswamy H. Sarma传达。

The Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) serves as a molecular switch, cycling between guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound states. KRAS modulates numerous signal transduction pathways including the conventional RAF-MEK-ERK pathway. Mutations in the RAS genes have been linked to the formation of malignant tumors. Human malignancies typically show mutations in the Ras gene including HRAS, KRAS, and NRAS. Among all the mutations in exon 12 and exon 13 of the KRAS gene, the G12D mutation is more prevalent in pancreatic and lung cancer and accounts for around 41% of all G12 mutations, making them potential anticancer therapeutic targets. The present study is aimed at repurposing the peptide inhibitor KD2 of the KRAS G12D mutant. We employed an in-silico mutagenesis approach to design novel peptide inhibitors from the experimentally reported peptide inhibitor, and it was found that substitutions (N8W, N8I, and N8Y) might enhance the peptide's binding affinity toward the KRAS. Molecular dynamics simulations and binding energy calculations confirmed that the newly designed peptide inhibitors are stable and that their binding affinities are stronger as compared to the wild-type peptide. The detailed analysis revealed that newly designed peptides have the potential to inhibit KRAS/Raf interaction and the oncogenic signal of the KRAS G12D mutant. Our findings strongly suggest that these peptides should be tested and clinically validated to combat the oncogenic activity of KRAS.Communicated by Ramaswamy H. Sarma.