Molecular Simulation of αvβ6 Integrin Inhibitors

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.特发性肺纤维化（idiopathic pulmonary fibrosis, IPF）作为一种慢性肺部疾病，其新型治疗手段的迫切需求推动了针对RGD结合整合素αvβ6的拮抗剂研究——该蛋白与该疾病的发生及进展密切相关。针对与天然配体pro-TGF-β1结合的αvβ6复合物开展的分子动力学（molecular dynamics, MD）模拟显示，随时间持续存在两种相互作用：双齿精氨酸-天冬氨酸配体-受体相互作用，以及配体上天冬氨酸与活性位点内Mg²+离子之间的金属螯合相互作用，这正是RGD结合配体的典型特征。此外，研究还鉴定出静态晶体结构中未观测到的额外结合位点相互作用。本研究针对一款RGD模拟物展开探究，该物质可作为一系列潜在αvβ6拮抗剂的骨架。该骨架包含一种广泛应用的1,8-萘啶衍生物，本研究为其提供了力场参数，以支持分子动力学及相对自由能微扰（relative free energy perturbation, FEP）模拟。分子动力学模拟结果凸显了氢键与阳离子-π相互作用的重要性。相对自由能微扰计算所预测的相对结合亲和力与实验值的平均偏差在1.5 kcal·mol⁻¹以内。