Gorse A D, Gready J E
Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra.
Protein Eng. 1997 Jan;10(1):23-30. doi: 10.1093/protein/10.1.23.
Orientations of the deazapterin ring and the conformational preferences of groups appended to the deazapterin ring in a set of 8-substituted deazapterin cations docked into the dihydrofolate reductase (DHFR) binding site have been investigated using a methodology based on the simulated annealing technique within molecular dynamics (MD) simulations. Of five possible binding pockets for the 8-substituents, identified from a preliminary manual docking study, one has been definitively eliminated after an analysis of MD trajectories, while another remains uncertain. Using a new method based on standard thermodynamic cycles and a linear approximation of polar and non-polar free energy contributions from MD averages, binding affinities of the different ligands in each binding site have been correlated with experimental dissociation constants. The study has provided insights into structure-activity relationships for use in the design of modified inhibitors of DHFR.
利用分子动力学（MD）模拟中基于模拟退火技术的方法，研究了一组对接至二氢叶酸还原酶（DHFR）结合位点的8-取代脱氮蝶呤阳离子中脱氮蝶呤环的取向以及连接至脱氮蝶呤环上的基团的构象偏好。从初步的手动对接研究中确定的8-取代基的五个可能结合口袋中，在对MD轨迹进行分析后，其中一个已被明确排除，而另一个仍不确定。使用基于标准热力学循环以及MD平均值的极性和非极性自由能贡献的线性近似的新方法，每个结合位点中不同配体的结合亲和力已与实验解离常数相关联。该研究为用于设计DHFR修饰抑制剂的构效关系提供了见解。
