Abu Hammad Areej M, Afifi Fatma U, Taha Mutasem O
Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, Queen Rania Street, Amman 11942, Jordan.
J Mol Graph Model. 2007 Sep;26(2):443-56. doi: 10.1016/j.jmgm.2007.02.002. Epub 2007 Feb 11.
In this project, several docking conditions, scoring functions and corresponding protein-aligned molecular field analysis (CoMFA) models were evaluated for a diverse set of neuraminidase (NA) inhibitors. To this end, a group of inhibitors were docked into the active site of NA. The docked structures were utilized to construct a corresponding protein-aligned CoMFA models by employing probe-based (H+, OH, CH3) energy grids and genetic partial least squares (G/PLS) statistical analysis. A total of 16 different docking configurations were evaluated, of which some succeeded in producing self-consistent and predictive CoMFA models. However, the best model coincided with docking the ionized ligands into the hydrated form of the binding site via PLP1 scoring function (r2LOO=0.735, r2PRESS against 24 test compounds=0.828). The highest-ranking CoMFA models were employed to probe NA-ligand interactions. Further validation by comparison with a co-crystallized ligand-NA crystallographic structure was performed. This combination of docking/scoring/CoMFA modeling provided interesting insights into the binding of different NA inhibitors.
在本项目中，针对多种神经氨酸酶（NA）抑制剂评估了几种对接条件、评分函数以及相应的蛋白比对分子场分析（CoMFA）模型。为此，将一组抑制剂对接至NA的活性位点。通过使用基于探针（H⁺、OH、CH₃）的能量网格和遗传偏最小二乘法（G/PLS）统计分析，利用对接结构构建相应的蛋白比对CoMFA模型。共评估了16种不同的对接构型，其中一些成功构建了自洽且具有预测性的CoMFA模型。然而，最佳模型是通过PLP1评分函数将离子化配体对接至结合位点的水合形式（留一法交叉验证系数r²LOO = 0.735，针对24种测试化合物的预测残差平方和r²PRESS = 0.828）。采用排名最高的CoMFA模型探究NA与配体的相互作用。通过与共结晶配体 - NA晶体结构进行比较进一步验证。这种对接/评分/CoMFA建模的组合为不同NA抑制剂的结合提供了有趣的见解。
