National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 03760, Korea.
Curr Top Med Chem. 2018;18(27):2313-2324. doi: 10.2174/1568026619666181220111059.
A series of imidazothiazole and oxazolopyridine derivatives as human Silent Information Regulator 1 (SIRT1) activators were subjected to the integrated 2D and 3D QSAR approaches. The derived 3D QSAR models yielded high cross-validated q2 values of 0.682 and 0.628 for CoMFA and CoMSIA, respectively. The non-cross validated values of r2 training = 0.89; predictive r2 test = 0.69 for CoMFA and r2=0.87; predictive r2 test =0.67 for CoMSIA reflected the statistical significance of the developed model. The steric, electrostatic, hydrophobic and hydrogen bond acceptor interactions have been found important in describing the variation in human SIRT1 activation. Further, 2D QSAR model for the same dataset yielded high statistical significance and derived 2D model's parameters corroborated with the 3D model in terms of features. Derived model was also validated by the crystal structure of active conformation of SIRT1. Developed models may be useful for the identification of potential novel human SIRT1 activators as a therapeutic agent.
一系列咪唑并噻唑和噁唑并吡啶衍生物作为人类沉默信息调节因子 1（SIRT1）激活剂，采用了整合的二维和三维 QSAR 方法进行研究。所得到的三维 QSAR 模型分别产生了 CoMFA 和 CoMSIA 的高交叉验证 q2 值为 0.682 和 0.628。CoMFA 的非交叉验证值 r2 训练=0.89；预测 r2 测试=0.69，CoMSIA 的 r2=0.87；预测 r2 测试=0.67，反映了所开发模型的统计学意义。立体、静电、疏水和氢键接受相互作用对于描述人类 SIRT1 激活的变化被认为是重要的。此外，对于同一数据集的二维 QSAR 模型也产生了高度的统计学意义，并且衍生的二维模型的参数与三维模型在特征方面是一致的。所开发的模型还通过 SIRT1 的活性构象的晶体结构进行了验证。所开发的模型可能有助于鉴定潜在的新型人类 SIRT1 激活剂作为治疗剂。
