Molecular Simulation of αvβ6 Integrin Inhibitors.,Journal of Chemical Information and Modeling

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Molecular Simulation of αvβ6 Integrin Inhibitors.
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2020-05-18 , DOI: 10.1021/acs.jcim.0c00254
Ellen E Guest ₁ , Steven A Oatley ₁ , Simon J F Macdonald ₂ , Jonathan D Hirst ₁

Affiliation

The urgent need for new treatments for the chronic lung disease idiopathic pulmonary fibrosis (IPF) motivates research into antagonists of the RGD binding integrin αvβ6, a protein linked to the initiation and progression of the disease. Molecular dynamics (MD) simulations of αvβ6 in complex with its natural ligand, pro-TGF-β1, show the persistence over time of a bidentate Arg-Asp ligand–receptor interaction and a metal chelate interaction between an aspartate on the ligand and an Mg²⁺ ion in the active site. This is typical of RGD binding ligands. Additional binding site interactions, which are not observed in the static crystal structure, are also identified. We investigate an RGD mimetic, which serves as a framework for a series of potential αvβ6 antagonists. The scaffold includes a derivative of the widely utilized 1,8-naphthyridine moiety, for which we present force field parameters, to enable MD and relative free energy perturbation (FEP) simulations. The MD simulations highlight the importance of hydrogen bonding and cation-π interactions. The FEP calculations predict relative binding affinities, within 1.5 kcal mol^–1, on average, of experiments.

中文翻译：

αvβ6 整合素抑制剂的分子模拟。

对慢性肺病特发性肺纤维化 (IPF) 新疗法的迫切需求促使人们研究 RGD 结合整合素 αvβ6 的拮抗剂，该蛋白与疾病的发生和进展有关。αvβ6 与其天然配体 pro-TGF-β1 复合的分子动力学 (MD) 模拟显示随着时间的推移，双齿 Arg-Asp 配体-受体相互作用以及配体上的天冬氨酸与 Mg 之间的金属螯合物相互作用持续存在²⁺活性位点的离子。这是典型的 RGD 结合配体。还确定了在静态晶体结构中未观察到的其他结合位点相互作用。我们研究了 RGD 模拟物，它作为一系列潜在 αvβ6 拮抗剂的框架。该支架包括广泛使用的 1,8-萘啶部分的衍生物，我们为此提供了力场参数，以实现 MD 和相对自由能扰动 (FEP) 模拟。MD 模拟强调了氢键和阳离子-π 相互作用的重要性。FEP 计算预测相对结合亲和力，平均在 1.5 kcal mol ^{–1范围内，实验。}

更新日期：2020-05-18

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