铃蟾肽是一种内源性肽，参与广泛的生理活动，从饱腹感、中枢神经系统昼夜节律控制和体温调节，到刺激胃肠道激素释放、巨噬细胞激活以及对外周组织发育的影响。该肽的作用是通过两个高亲和力 G 蛋白偶联受体 BB1R 和 BB2R 介导的。在病理生理条件下，这些受体在许多不同类型的肿瘤中过度表达，例如前列腺癌、乳腺癌、小细胞和非小细胞肺癌和胰腺癌。这一观察结果已用于设计细胞标记物，但尚未用于治疗目的。尽管该肽具有巨大的生物学意义，但对其活性的立体化学特征却知之甚少。一方面，诱变研究确定了一些对高铃蟾肽亲和力很重要的受体残基，另一方面，一些研究重点关注肽的不同残基与受体激活的相关性。与 BB1R 和 BB2R 结合的肽模型有助于提高我们对赋予铃蟾肽活性的立体化学特征的理解。因此，本研究描述了使用肽及其受体模型，通过引导分子动力学构建此类模型的计算过程。目前的结果为铃蟾肽及其受体的结构-活性关系提供了新的见解，并解释了观察到的对 BB1R 和 BB2R 的不同结合亲和力。最后，可以进一步利用这些模型来帮助设计具有改进的药代动力学特征的新型小分子肽模拟物。版权所有 © 2023。由 Elsevier B.V. 出版。

Bombesin is an endogenous peptide involved in a wide spectrum of physiological activities ranging from satiety, control of circadian rhythm and thermoregulation in the central nervous system, to stimulation of gastrointestinal hormone release, activation of macrophages and effects on development in peripheral tissues. Actions of the peptide are mediated through the two high affinity G-protein coupled receptors BB1R and BB2R. Under pathophysiological conditions, these receptors are overexpressed in many different types of tumors, such as prostate cancer, breast cancer, small and non-small cell lung cancer and pancreatic cancer. This observation has been used for designing cell markers, but it has not been yet exploited for therapeutical purposes. Despite the enormous biological interest of the peptide, little is known about the stereochemical features that contribute to their activity. On the one hand, mutagenesis studies identified a few receptor residues important for high bombesin affinity and on the other, a few studies focused on the relevance of diverse residues of the peptide for receptor activation. Models of the peptide bound to BB1R and BB2R can be helpful to improve our understanding of the stereochemical features granting bombesin activity. Accordingly, the present study describes the computational process followed to construct such models by means of Steered Molecular Dynamics, using models of the peptide and its receptors. Present results provide new insights into the structure-activity relationships of bombesin and its receptors, as well as render an explanation for the differential binding affinity observed towards BB1R and BB2R. Finally, these models can be further exploited to help for designing novel small molecule peptidomimetics with improved pharmacokinetics profile.Copyright © 2023. Published by Elsevier B.V.