Bostancioglu Safiye Merve, Acar Ahmet
Department of Biology, Faculty of Arts and Sciences, Marmara University, Goztepe Campus, Goztepe, Istanbul, 34722, Turkey.
Department of Biological Sciences, Middle East Technical University, Universiteler Mah. Dumlupınar Bulvarı 1, Çankaya, Ankara, 06800, Turkey.
BMC Res Notes. 2025 Jul 12;18(1):287. doi: 10.1186/s13104-025-07137-y.
The RAS family, comprising KRAS, NRAS, and HRAS, plays a pivotal role in oncogenesis, dynamically regulating cellular processes through intricate cycling between active and inactive states. Despite recent advancements, direct therapeutic targeting of RAS proteins has proven challenging. Targeting KRASG12D with natural compounds offers a unique therapeutic potential, leveraging the structural diversity and bioactivity of natural compounds. In this study, we investigated the potential of natural products to target oncogenic KRASG12D mutant. Given the higher prevalence of KRASG12D mutations, our study employs structure-based virtual screening and molecular dynamics simulations to identify potential KRASG12D inhibitors within a natural compound library.
Two natural compounds, NPA019556 and NPA032945, demonstrated strong and stable binding interactions with KRASG12D, surpassing the performance of known inhibitor MRTX1133. After post-molecular dynamics analyses, which encompass Dynamic Cross-Correlation Matrix and Principal Component Analysis, additional evidence suggests that the flexible switch I (residues 30-40) and switch II (residues 58-72) regions demonstrate greater anti-correlation in NPA019556 and NPA032945 compared to MRTX1133 complexed with KRASG12D. These findings highlight the promise of two natural compounds, NPA019556 and NPA032945, as specific KRASG12D inhibitors, paving the way for future and therapeutic development.
由KRAS、NRAS和HRAS组成的RAS家族在肿瘤发生中起关键作用，通过在活性和非活性状态之间的复杂循环动态调节细胞过程。尽管最近取得了进展，但直接对RAS蛋白进行治疗性靶向已被证明具有挑战性。用天然化合物靶向KRASG12D具有独特的治疗潜力，利用了天然化合物的结构多样性和生物活性。在本研究中，我们研究了天然产物靶向致癌KRASG12D突变体的潜力。鉴于KRASG12D突变的较高发生率，我们的研究采用基于结构的虚拟筛选和分子动力学模拟，在天然化合物库中识别潜在的KRASG12D抑制剂。
两种天然化合物NPA019556和NPA032945与KRASG12D表现出强而稳定的结合相互作用，超过了已知抑制剂MRTX1133的性能。在进行包括动态交叉相关矩阵和主成分分析的分子动力学后分析后，更多证据表明，与与KRASG12D复合的MRTX1133相比，NPA019556和NPA032945中灵活的开关I（30-40位残基）和开关II（58-72位残基）区域表现出更大的反相关性。这些发现突出了两种天然化合物NPA019556和NPA032945作为特异性KRASG12D抑制剂的前景，为未来的治疗发展铺平了道路。
