Departamento de Química, Universidade Federal de Lavras, Lavras, MG, Brazil.
Eur J Med Chem. 2009 Nov;44(11):4344-52. doi: 10.1016/j.ejmech.2009.05.016. Epub 2009 May 23.
The three-dimensional quantitative structure-activity relationships (3D-QSAR) of a series of HOE/BAY-793 analogs (C(2)-symmetric diol peptidomimetics), developed by Budt and co-workers [Bioorg. Med. Chem. 3 (1995) 559] as inhibitors of HIV-1 protease (HIV-PR), were studied using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). Theoretical active conformers for these peptidomimetics were generated, derived from modeled protease inhibitor complexes, in order to orient the compounds superposition and to afford a consistent alignment. The best CoMFA model (N=27, q(2)=0.637, R(2)=0.991) showed contributions of the steric (45.7%) and electrostatic (54.3%) fields to the activity, while the best CoMSIA model (N=27, q(2)=0.511, R(2)=0.987) showed contributions of the electrostatic (68.5%) and hydrogen bond donor (37.5%) fields. The models were also external validated using four compounds (test set) not included in the model generation process. The statistical parameters from both models indicate that the data are well fitted and have high predictive ability. Moreover, the resulting 3D CoMFA/CoMSIA contour maps provide useful guidance for designing highly active ligands. The CoMFA/CoMSIA models were also compared with previous 4D-QSAR models [E.F.F. da Cunha, M.G. Albuquerque, O.A.C. Antunes, R.B. de Alencastro, QSAR Comb. Sci. 24 (2005), 240-253.].
布特及其同事研究了一系列 HOE/BAY-793 类似物（C(2)-对称二醇肽模拟物）的三维定量构效关系（3D-QSAR），这些类似物被开发为 HIV-1 蛋白酶（HIV-PR）的抑制剂[Bioorg. Med. Chem. 3 (1995) 559]。使用比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）研究了这些肽模拟物的三维定量构效关系。为了使化合物叠合定向并提供一致的对准，从模拟的蛋白酶抑制剂复合物中生成了这些肽模拟物的理论活性构象。最佳 CoMFA 模型（N=27，q(2)=0.637，R(2)=0.991）显示出立体（45.7%）和静电（54.3%）场对活性的贡献，而最佳 CoMSIA 模型（N=27，q(2)=0.511，R(2)=0.987）显示出静电（68.5%）和氢键供体（37.5%）场的贡献。还使用未包含在模型生成过程中的四个化合物（测试集）对模型进行了外部验证。两个模型的统计参数表明，数据拟合良好，具有较高的预测能力。此外，所得的 3D CoMFA/CoMSIA 等高线图为设计高活性配体提供了有用的指导。还将 CoMFA/CoMSIA 模型与以前的 4D-QSAR 模型进行了比较[E.F.F. da Cunha、M.G. Albuquerque、O.A.C. Antunes、R.B. de Alencastro、QSAR Comb. Sci. 24 (2005)，240-253]。
