基于多肽的肌醇需要酶 1 计算机辅助药物设计

Alireza Ghanbari, Amir Norouzy, N. Balmeh, Najaf Allahyari Fard, M. Moosavi
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摘要

肌醇需要酶 1(IRE1)是一种内质网(ER)跨膜蛋白,具有激酶和内切酶活性,在ER应激及其随后的未折叠蛋白反应(UPR)中发挥着重要作用。最近的证据表明,IRE1 信号传导有助于肿瘤发生和癌症进展,这表明了 UPR 这一保守臂的治疗重要性。在这里,我们采用了不同的计算工具来设计和预测能够破坏 IRE1 二聚化/异构化的短肽,作为抑制其激酶和 RNase 活性的一种策略。利用 mCSM-PPI2 和 OSPREY 3.0 构建了一个基于突变的多肽库。使用 HADDOCK 2.2 在线服务器对设计的多肽与 IRE1 蛋白进行了分子相互作用分析,然后使用 GROMACS 2020 软件包进行了分子动力学分析。然后,我们选出了与 IRE1 复合物具有高亲和力和最佳预测理化性质的候选短肽。最后,我们使用在线服务器(如 ToxinPred 和 AllerTop)来确定没有明显过敏性或细胞毒性的最佳候选多肽。这些合理设计的多肽具有与 IRE1 寡聚化结构域结合的能力,可被视为潜在的候选药物,用于干扰 IRE1 在癌症和相关疾病中的活性,有待进一步的硅学和实验研究验证。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Computer-aided peptide-based drug design for inositol-requiring enzyme 1
Inositol-requiring enzyme 1 (IRE1), an endoplasmic reticulum (ER) transmembrane protein with both kinase and endoribonuclease activities, plays an essential role during ER stress and its subsequent unfolded protein response (UPR). Recent evidence shows IRE1 signaling contributes to tumorigenesis and cancer progression, pointing to the therapeutic importance of this conserved arm of the UPR. Here, we employed different computational tools to design and predict short peptides with the capability of disrupting IRE1 dimerization/oligomerization, as a strategy for inhibiting its Kinase and RNase activities. A mutation-based peptide library was constructed using mCSM-PPI2 and OSPREY 3.0. The molecular interaction analyses between the designed peptides and IRE1 protein were conducted using the HADDOCK 2.2 online server, followed with molecular dynamics analysis by the GROMACS 2020 package. We then selected short peptide candidates that exhibited high affinity and best predicted physicochemical properties in complex with IRE1. Finally, online servers, such as ToxinPred and AllerTop, were used to identify the best peptide candidates that showed no significant allergenic or cytotoxic properties. These rational designed peptides with the capability of binding to IRE1 oligomerization domain can be considered as potential drug candidates for disrupting IRE1 activity in cancer and related diseases, pending for further validation by in silico and experimental studies.
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