Slater Olivia, Kontoyianni Maria
Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University, Edwardsville, IL 62026, USA.
Org Biomol Chem. 2025 Aug 8. doi: 10.1039/d5ob00775e.
Somatotropin-release Inhibiting Factor (SRIF) binds somatostatin subtype-4 receptor (sst4) within the neocortex to increase amyloid beta catabolism, and possibly effects neuronal plaque formation and disease progression of Alzheimer's disease. Recently, sst4 in complex with SRIF or a small molecule agonist were resolved using cryo-EM, and mutagenesis identified amino acid residues that contributed to activity. In the present study, we used mixed Quantum Mechanics/Molecular Mechanics (QM/MM) to refine the experimental sst4 complexes and decipher agonist-sst4 interactions. SRIF rendered the complex more stable, while interactions with asparagines 199 and 293 seen in the experimental complexes were lost and replaced with Gln279. We also addressed long-standing questions related to sst4 agonist binding. Toward that end, we used quantum mechanics, molecular docking, and QM/MM refinement methods and employed pair-wise comparisons or matched molecular pairs to explore the effects of chemical substitutions on ligand properties and energetics. We identified amino acid interactions that were consistent among all refined complexes, and those that differentiated high affinity binders. Finally, we considered several parameters to discern which correlated best with affinity, and highlighted aspects often overlooked or yet to be explored in order to enhance lead optimization outcomes.
生长激素释放抑制因子（SRIF）与新皮质内的生长抑素4型受体（sst4）结合，以增加β-淀粉样蛋白的分解代谢，并可能影响阿尔茨海默病的神经元斑块形成和疾病进展。最近，利用冷冻电镜解析了与SRIF或小分子激动剂结合的sst4复合物，诱变鉴定出了对活性有贡献的氨基酸残基。在本研究中，我们使用量子力学/分子力学混合方法（QM/MM）来优化实验得到的sst4复合物，并解读激动剂与sst4的相互作用。SRIF使复合物更稳定，而在实验复合物中观察到的与天冬酰胺199和293的相互作用消失，取而代之的是谷氨酰胺279。我们还解决了与sst4激动剂结合相关的长期问题。为此，我们使用量子力学、分子对接和QM/MM优化方法，并采用成对比较或匹配分子对来探索化学取代对配体性质和能量学的影响。我们确定了所有优化复合物中一致的氨基酸相互作用，以及区分高亲和力结合剂的相互作用。最后，我们考虑了几个参数，以辨别哪个参数与亲和力最相关，并强调了为提高先导优化结果而经常被忽视或尚未探索的方面。
