Introduction: Short bowel syndrome (SBS) is a disabling condition that occurs following the loss of substantial portions of the intestine, leading to inadequate absorption of nutrients and fluids. Teduglutide is the only drug that has been FDA-approved for long-term treatment of SBS. This medicine exerts its biological effects through binding to the GLP-2 receptor.

Methods: The current study aimed to use computational mutagenesis approaches to design novel potent analogues of teduglutide. To this end, the constructed teduglutide-GLP2R 3D model was subjected to the alanine scanning mutagenesis where ARG²⁰, PHE²², ILE²³, LEU²⁶, ILE²⁷ and LYS³⁰ were identified as the key amino acids involved in ligand-receptor interaction. In order to design potent teduglutide analogues, using MAESTROweb machine learning method, the residues of teduglutide were virtually mutated into all naturally occurring amino acids and the affinity improving mutations were selected for further analysis using PDBePISA methodology which interactively investigates the interactions established at the interfaces of macromolecules.

Results: The calculations resulted in D15I, D15L, D15M and N24M mutations, which can improve the binding ability of the ligand to the receptor. The final evaluation of identified mutations was performed by molecular dynamics simulations, indicating that D15I and D15M are the most reliable mutations to increase teduglutide affinity towards its receptor.

Conclusion: The findings in the current study may facilitate designing more potent teduglutide analogues leading to the development of novel treatments in short bowel syndrome.

简介：短肠综合征 (SBS) 是一种致残疾病，在肠道的大部分损失后发生，导致营养和液体吸收不足。替度鲁肽是唯一获得 FDA 批准用于长期治疗 SBS 的药物。该药物通过与 GLP-2 受体结合来发挥其生物学作用。

方法：目前的研究旨在使用计算诱变方法来设计新型强效替度鲁肽类似物。为此，对构建的 teduglutide-GLP2R 3D 模型进行丙氨酸扫描诱变，其中 ARG ²⁰、PHE ²²、ILE ²³、LEU ²⁶、ILE ²⁷和 LYS ³⁰被鉴定为参与配体-受体相互作用的关键氨基酸。为了设计有效的 teduglutide 类似物，使用 MAESTROweb 机器学习方法，将 teduglutide 的残基几乎突变为所有天然存在的氨基酸，并使用 PDBePISA 方法选择亲和力提高突变进行进一步分析，该方法交互式地研究了在界面上建立的相互作用大分子。

结果：计算导致D15I、D15L、D15M和N24M突变，可提高配体与受体的结合能力。通过分子动力学模拟对已鉴定的突变进行最终评估，表明 D15I 和 D15M 是最可靠的突变，可增加 teduglutide 对其受体的亲和力。

结论：当前研究中的发现可能有助于设计更有效的替度鲁肽类似物，从而开发新的短肠综合征治疗方法。