Department of Mechanical Engineering, University of Alberta, Edmonton, AB, T6G 1H9, Canada.
Departments of Biological Sciences and Computing Science, University of Alberta, Edmonton, AB, T6G 2E8, Canada.
J Comput Aided Mol Des. 2019 Oct;33(10):913-926. doi: 10.1007/s10822-019-00239-3. Epub 2019 Nov 4.
Misfolded Cu/Zn superoxide dismutase enzyme (SOD1) shows prion-like propagation in neuronal cells leading to neurotoxic aggregates that are implicated in amyotrophic lateral sclerosis (ALS). Tryptophan-32 (W32) in SOD1 is part of a potential site for templated conversion of wild type SOD1. This W32 binding site is located on a convex, solvent exposed surface of the SOD1 suggesting that hydration effects can play an important role in ligand recognition and binding. A recent X-ray crystal structure has revealed that 5-Fluorouridine (5-FUrd) binds at the W32 binding site and can act as a pharmacophore scaffold for the development of anti-ALS drugs. In this study, a new protocol is developed to account for structural (non-displaceable) water molecules in docking simulations and successfully applied to predict the correct docked conformation binding modes of 5-FUrd at the W32 binding site. The docked configuration is within 0.58 Å (RMSD) of the observed configuration. The docking protocol involved calculating a hydration structure around SOD1 using molecular theory of solvation (3D-RISM-KH, 3D-Reference Interaction Site Model-Kovalenko-Hirata) whereby, non-displaceable water molecules are identified for docking simulations. This protocol was also used to analyze the hydrated structure of the W32 binding site and to explain the role of solvation in ligand recognition and binding to SOD1. Structural water molecules mediate hydrogen bonds between 5-FUrd and the receptor, and create an environment favoring optimal placement of 5-FUrd in the W32 binding site.
错误折叠的铜/锌超氧化物歧化酶（SOD1）在神经元细胞中表现出类似朊病毒的传播，导致神经毒性聚集物，这些聚集物与肌萎缩侧索硬化症（ALS）有关。SOD1 中的色氨酸-32（W32）是野生型 SOD1 模板转换的潜在位点之一。这个 W32 结合位点位于 SOD1 的凸面、溶剂暴露表面上，这表明水合作用可以在配体识别和结合中发挥重要作用。最近的 X 射线晶体结构揭示，5-氟尿嘧啶（5-FUrd）结合在 W32 结合位点上，并可以作为开发抗 ALS 药物的药效团支架。在这项研究中，开发了一种新的方案来考虑对接模拟中的结构（不可置换）水分子，并成功地应用于预测 5-FUrd 在 W32 结合位点的正确对接构象结合模式。对接构型与观察到的构型之间的 RMSD 为 0.58Å。对接方案涉及使用溶剂化的分子理论（3D-RISM-KH、3D-参考相互作用位点模型-Kovalenko-Hirata）计算 SOD1 周围的水合结构，从而确定用于对接模拟的不可置换水分子。该方案还用于分析 W32 结合位点的水合结构，并解释溶剂化在配体识别和与 SOD1 结合中的作用。结构水分子介导 5-FUrd 和受体之间的氢键，并创造有利于 5-FUrd 在 W32 结合位点中最佳放置的环境。
