Diabetes mellitus significantly contributes to breast cancer progression, where hyperglycemia upregulates specific genes, leading to more aggressive tumor growth. In patients with BC that develop diabetes, neuregulin 1 (NRG1) and epidermal growth factor receptor 3 (ERBB3) overexpression exacerbate tumor growth and progression. Since the interaction between NRG1 and ERBB3 is critical for tumor growth, understanding the molecular mechanisms underlying NRG1–ERBB3 complex formation is essential for elucidating diabetes-assisted breast cancer progression. However, the key residues forming the NRG1–ERBB3 complex remain unknown. Here, we substituted specific residues in NRG1 with alanine and studied its interactions with ERBB3 using computational structural biology tools. We further screened the South African natural compounds database to target the complex’s interface residues to discover potential inhibitors. The conformational stability and dynamic features of NRG1–WT, –H2A, –L3A, and –K35A complexed with ERBB3 were subjected to 400 ns molecular dynamics simulations. The free binding energies of all NRG1–ERBB3 complexes were calculated using the molecular mechanics-generalized Born surface area (MM/GBSA). The H2 and L3 alanine substitutions caused a loss of interaction with ERBB3 residue D73, weakening the interaction with ERBB3. Screening 1300 natural compounds identified four (SANC00643, SANC00824, SANC00975, and SANC00335) with the best potential to inhibit ERRB3-NRG1 coupling. The binding free energies for each complex were − 48.55 kcal/mol for SANC00643, − 47.68 kcal/mol for SANC00824, − 46.04 kcal/mol for SANC00975, and − 45.29 kcal/mol for SANC00335, showing their overall stronger binding with ERBB3 than NRG1 and their potential to act as ERBB3-NRG1 complex inhibitors. In conclusion, this complex may represent a residue-specific drug target to inhibit BC progression.

Graphical abstract

中文翻译：

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探索 NRG1-ERBB3 复合物的结合机制并发现有效的天然产物以减少糖尿病辅助乳腺癌的进展

糖尿病对乳腺癌的进展有显着影响，高血糖会上调特定基因，导致肿瘤生长更具侵袭性。在患有糖尿病的 BC 患者中，神经调节蛋白 1 ( NRG1 ) 和表皮生长因子受体 3 ( ERBB3 ) 过度表达会加剧肿瘤的生长和进展。由于 NRG1 和 ERBB3 之间的相互作用对于肿瘤生长至关重要，因此了解 NRG1-ERBB3 复合物形成的分子机制对于阐明糖尿病辅助的乳腺癌进展至关重要。然而，形成 NRG1-ERBB3 复合物的关键残基仍然未知。在这里，我们用丙氨酸取代了 NRG1 中的特定残基，并使用计算结构生物学工具研究了其与 ERBB3 的相互作用。我们进一步筛选了南非天然化合物数据库，以复合物的界面残基为目标，发现潜在的抑制剂。对与 ERBB3 复合的 NRG1–WT、–H2A、–L3A 和 –K35A 的构象稳定性和动态特征进行了 400 ns 分子动力学模拟。所有NRG1-ERBB3复合物的自由结合能均使用分子力学广义玻恩表面积（MM/GBSA）计算。H2和L3丙氨酸取代导致与ERBB3残基D73的相互作用丧失，削弱了与ERBB3的相互作用。通过筛选 1300 种天然化合物，确定了四种（SANC00643、SANC00824、SANC00975 和 SANC00335）最有可能抑制 ERRB3-NRG1 偶联。每个复合物的结合自由能分别为：SANC00643 为 - 48.55 kcal/mol，SANC00824 为 - 47.68 kcal/mol，SANC00975 为 - 46.04 kcal/mol，SANC00335 为 - 45.29 kcal/mol，表明它们与 ERBB3 的结合总体强于 NRG1及其作为 ERBB3-NRG1 复合物抑制剂的潜力。总之，该复合物可能代表抑制 BC 进展的残留特异性药物靶点。

图形概要