分子动力学模拟揭示放射性药物与生长抑素受体 2 的相互作用,Journal of Chemical Information and Modeling

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分子动力学模拟揭示放射性药物与生长抑素受体 2 的相互作用
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2023-07-19 , DOI: 10.1021/acs.jcim.3c00712
Silvia Gervasoni ₁ , Işılay Öztürk ₁ , Camilla Guccione ₁ , Andrea Bosin ₁ , Paolo Ruggerone ₁ , Giuliano Malloci ₁

Affiliation

生长抑素受体 2 (SSTR2) 通常在神经内分泌肿瘤中过度表达，针对该受体的药物开发是深入研究的焦点。一些与放射性核素结合的分子在临床上用于诊断和治疗目的。这些放射性药物由与带有放射性核素的螯合剂部分缀合的生长抑素类似物生物载体组成。迄今为止，尽管付出了宝贵的努力，但放射性药物与 SSTR2 复合物相互作用的详细分子水平描述尚未完成。因此，在这项工作中，我们仔细分析了 SSTR2 与六种放射性药物化合物复合物的关键动力学特征和详细的分子相互作用，这些化合物选自少数已使用的放射性药物化合物（ 64 Cu/ 68 Ga-DOTATATE、 68 ^Ga - ^DOTATOC、⁶⁴ Cu ^- SARTATE ）以及一些处于临床开发阶段（⁶⁸ Ga-DOTANOC、⁶⁴ Cu-TETATATE）。通过分子动力学模拟和利用最近可用的 SSTR2 结构，我们探索了化合物的不同部分（肽、放射性核素和螯合剂）在与受体相互作用中的影响。我们确定了最稳定的结合模式，并发现了表征六种化合物的独特相互作用模式。因此，我们揭示了对于识别此类放射性药物至关重要的详细分子相互作用。本研究中提出的显微镜下有充分依据的分析为设计针对 SSTR2 的新型有效配体提供了指导。

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Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations

The development of drugs targeting somatostatin receptor 2 (SSTR2), generally overexpressed in neuroendocrine tumors, is focus of intense research. A few molecules in conjugation with radionuclides are in clinical use for both diagnostic and therapeutic purposes. These radiopharmaceuticals are composed of a somatostatin analogue biovector conjugated to a chelator moiety bearing the radionuclide. To date, despite valuable efforts, a detailed molecular-level description of the interaction of radiopharmaceuticals in complex with SSTR2 has not yet been accomplished. Therefore, in this work, we carefully analyzed the key dynamical features and detailed molecular interactions of SSTR2 in complex with six radiopharmaceutical compounds selected among the few already in use (⁶⁴Cu/⁶⁸Ga-DOTATATE, ⁶⁸Ga-DOTATOC, ⁶⁴Cu-SARTATE) and some in clinical development (⁶⁸Ga-DOTANOC, ⁶⁴Cu-TETATATE). Through molecular dynamics simulations and exploiting recently available structures of SSTR2, we explored the influence of the different portions of the compounds (peptide, radionuclide, and chelator) in the interaction with the receptor. We identified the most stable binding modes and found distinct interaction patterns characterizing the six compounds. We thus unveiled detailed molecular interactions crucial for the recognition of this class of radiopharmaceuticals. The microscopically well-founded analysis presented in this study provides guidelines for the design of new potent ligands targeting SSTR2.

更新日期：2023-07-19

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