Abstract：
Cancer poses a significant global health challenge and significantly contributes to mortality. NEK7, related to the NIMA protein kinase family, plays a crucial role in spindle assembly and cell division. The dysregulation of NEK7 is closely linked to the onset and progression of various cancers, especially colon and breast cancer, making it a promising target for cancer therapy. Nevertheless, the shortage of high-quality NEK7 inhibitors highlights the need for new therapeutic strategies. In this study, we utilized a multidisciplinary approach, including virtual screening, molecular docking, pharmacokinetics, molecular dynamics simulations (MDs), and MM/PBSA calculations, to evaluate natural compounds as NEK7 inhibitors comprehensively. Through various docking strategies, we identified three natural compounds: (-)-balanol, digallic acid, and scutellarin. Molecular docking revealed significant interactions at residues such as GLU112 and ALA114, with docking scores of -15.054, -13.059, and -11.547 kcal/mol, respectively, highlighting their potential as NEK7 inhibitors. MDs confirmed the stability of these compounds at the NEK7-binding site. Hydrogen bond analysis during simulations revealed consistent interactions, supporting their strong binding capacity. MM/PBSA analysis identified other crucial amino acids contributing to binding affinity, including ILE20, VAL28, ILE75, LEU93, ALA94, LYS143, PHE148, LEU160, and THR161, crucial for stabilizing the complex. This research demonstrated that these compounds exceeded dabrafenib in binding energy, according to MM/PBSA calculations, underscoring their effectiveness as NEK7 inhibitors. ADME/T predictions showed lower oral toxicity for these compounds, suggesting their potential for further development. This study highlights the promise of these natural compounds as bases for creating more potent derivatives with significant biological activities, paving the way for future experimental validation.
摘要：
癌症构成了重大的全球健康挑战，并显著增加了死亡率。NEK7，与NIMA蛋白激酶家族相关，在纺锤体组装和细胞分裂中起着至关重要的作用。NEK7的失调与各种癌症的发生和进展密切相关，尤其是结肠癌和乳腺癌，使其成为癌症治疗的有希望的目标。然而，高质量NEK7抑制剂的短缺凸显了对新治疗策略的需求.在这项研究中,我们采用了多学科的方法，包括虚拟筛查，分子对接,药代动力学，分子动力学模拟(MD)，和MM/PBSA计算，综合评价天然化合物作为NEK7抑制剂。通过各种对接策略,我们确定了三种天然化合物：（-）-巴拉诺，双金属酸,还有Scutellarin.分子对接揭示了在诸如GLU112和ALA114的残基上的显着相互作用，对接评分为-15.054，-13.059和-11.547kcal/mol，分别,突出了它们作为NEK7抑制剂的潜力。MD证实了这些化合物在NEK7结合位点的稳定性。模拟过程中的氢键分析揭示了一致的相互作用，支持他们强大的约束力。MM/PBSA分析确定了其他有助于结合亲和力的关键氨基酸，包括ILE20，VAL28，ILE75，LEU93，ALA94，LYS143，PHE148，LEU160和THR161，对稳定复合物至关重要。这项研究表明，这些化合物的结合能超过了dabrafenib，根据MM/PBSA计算，强调它们作为NEK7抑制剂的有效性。ADME/T预测显示这些化合物的口服毒性较低，表明了他们进一步发展的潜力。这项研究强调了这些天然化合物作为创造具有显著生物活性的更有效衍生物的基础的前景。为未来的实验验证铺平了道路。
