核受体结合 SET 结构域蛋白 2 (NSD2) 显着促进癌症的发展，使其成为癌症药物发现的有希望的靶点。这项研究探索天然化合物作为 NSD2 在癌症治疗中的潜在选择性抑制剂。该研究采用综合计算机方法，利用药效团建模、分子对接、药代动力学分析和分子动力学模拟。使用第一个与 NSD2 结合的选择性和有效配体进行基于电子药效团模型的筛选，从 SuperNatural 3.0 数据库（包含 449,008 个分子）中鉴定出 49,248 种天然化合物，与已开发的药效团假设具有可接受的一致性。随后，进行分子对接以评估突出的化合物，从而根据以 G 分数表示的结合亲和力，选择了超过参考抑制剂的 10 种候选化合物。前三个命中（SN0450102、SN0410255 和 SN0142336）的配体-残基相互作用分析揭示了与 NSD2 活性位点的多种关键相互作用，包括氢键、pi-pi 堆积以及与 NSD2-PWWP1 中关键氨基酸残基的疏水接触领域。药代动力学分析证实了精制命中的药物敏感性，表明良好的细胞渗透性和最小的血脑屏障渗透性。 200 纳秒的分子动力学模拟证实了蛋白质-配体复合物的稳定性，均方根偏差和均方根波动分析的波动最小。总体而言，这项研究确定了有前景的天然化合物作为治疗 NSD2 相关癌症的潜在药物。版权所有：© 2024 Mohamed 等人。这是一篇根据知识共享署名许可条款分发的开放获取文章，允许在任何媒体上不受限制地使用、分发和复制，前提是注明原始作者和来源。

Nuclear receptor binding SET domain protein 2 (NSD2) significantly contributes to the development of cancer, making it a promising target for cancer drug discovery. This research explores natural compounds as potential selective inhibitors for NSD2 in cancer treatment. Employing a comprehensive in silico approach, the study utilized pharmacophore modeling, molecular docking, pharmacokinetic profiling, and molecular dynamics simulations. An e-pharmacophore model-based screening using the first selective and potent ligand bound to NSD2 identified 49,248 natural compounds from the SuperNatural 3.0 database (containing 449,008 molecules) with acceptable alignment with the developed pharmacophore hypotheses. Subsequently, molecular docking was executed to assess the standout compounds which led to the selection of ten candidates that surpassed the reference inhibitor in accordance w the binding affinity expressed as a G score. Ligand-residue interaction analyses of the top three hits (SN0450102, SN0410255, and SN0142336) revealed diverse crucial interactions with the NSD2 active site, including hydrogen bonds, pi-pi stacking, and hydrophobic contacts with key amino acid residues in the NSD2-PWWP1 domain. Pharmacokinetic profiling confirmed the drug-likability for the refined hits, indicating good cellular permeability and minimal blood-brain barrier penetration. Molecular dynamics simulations for 200 nanoseconds affirmed the stability of protein-ligand complexes, with minimal fluctuations in root mean square deviation and root mean square fluctuation analyses. Overall, this study identified promising natural compounds as potential pharmaceutical agents in the treatment of NSD2-associated cancers.Copyright: © 2024 Mohamed et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.