Exploring the Binding Mechanism of NRG1–ERBB3 Complex and Discovery of Potent Natural Products to Reduce Diabetes-Assisted Breast Cancer Progression

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: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12539-023-00566-y.