<i>In silico</i> identification of hydantoin derivatives: a novel natural prolyl hydroxylase inhibitor
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Alzheimer’s disease (AD) is the most common dementia in late life memory related issues. It is estimated that worldwide 46.8 million people suffer from dementia. The hypoxia inducible factor (HIF) upregulation could be a potential neuroprotective strategy by modulating the multiple survival pathways in AD. Hence, the development of small molecules that induce HIF-α activation via inhibition of prolyl hydroxylase enzyme (PHD) has been suggested as a potentially useful therapeutic strategy for the treatment of AD. Thus, to unveil a novel human PHD inhibitor, 2D-QSAR (Quantitative Structure Activity Relationship) modeling was performed with the 213 PHD inhibitors reported in the USA patent database. Best model with the <i>r</i><sup>2</sup> score of 0.8273 and <i>q</i><sup>2</sup> value of 0.8284 with dendritic fingerprint was developed and visualized by kernel partial least squares (KPLS) methods, which were used for visualization and screening of natural/derivative compounds database for novel and effective drug or scaffold. The docking was performed as a secondary strategy for screening the top 5000 compounds retrieved by 2D-QSAR based screening. Further, the docked complexes were screened by molecular dynamics (MD) simulation and molecular mechanics/generalized Born surface area (MM-GBSA) based binding free energy calculations to determine the binding energy of the inhibitors and to identify crucial interacting energy contributors. Three leads have demonstrated good binding free energy and the better binding affinity for PHD compared to other selected ligands. Thus, the results obtained from QSAR, docking and MD simulations depicted that hydantoin scaffold could be effectively used as a potent inhibitor toward human PHD in AD therapeutics. Communicated by Ramaswamy H. Sarma
阿尔茨海默病（Alzheimer’s disease, AD）是老年期最常见的以记忆相关障碍为核心表现的痴呆症。据估算，全球共有4680万痴呆症患者。缺氧诱导因子（hypoxia inducible factor, HIF）的上调可通过调控阿尔茨海默病中的多条细胞存活通路，成为潜在的神经保护策略。因此，通过抑制脯氨酰羟化酶（prolyl hydroxylase enzyme, PHD）以诱导HIF-α活化的小分子开发，已被提出作为治疗阿尔茨海默病的潜在有效治疗方案。 为挖掘新型人源PHD抑制剂，研究人员针对美国专利数据库中收录的213种PHD抑制剂开展了二维定量构效关系（2D-QSAR, Quantitative Structure Activity Relationship）建模。最终构建了基于树状指纹的最优模型，其决定系数r²为0.8273，交叉验证相关系数q²为0.8284，并通过核偏最小二乘（kernel partial least squares, KPLS）方法完成模型可视化。该模型被用于对天然产物及衍生物化合物数据库进行可视化筛选，以发掘新型高效药物或药物骨架。 作为二级筛选策略，研究人员对通过2D-QSAR筛选得到的前5000个化合物开展了分子对接实验。进一步地，研究人员通过分子动力学（molecular dynamics, MD）模拟以及基于分子力学/广义玻恩表面积（molecular mechanics/generalized Born surface area, MM-GBSA）的结合自由能计算，对对接得到的复合物进行筛选，以确定抑制剂的结合能并识别关键的相互作用能量贡献因子。 最终有3个先导化合物展现出良好的结合自由能，且相较于其他选定配体，对PHD具有更优的结合亲和力。综上，定量构效关系、分子对接及分子动力学模拟的研究结果表明，乙内酰脲骨架可作为靶向人源PHD的强效抑制剂，有效应用于阿尔茨海默病的治疗。本文由Ramaswamy H. Sarma通讯。
