期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2008
卷号：105
期号：30
页码：10378-10383
DOI：10.1073/pnas.0803847105
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：An explicitly polarizable force field based exclusively on quantum data is applied to calculations of relative binding affinities of ligands to proteins. Five ligands, differing by replacement of an atom or functional group, in complexes with three serine proteases--trypsin, thrombin, and urokinase-type plasminogen activator--with available experimental binding data are used as test systems. A special protocol of thermodynamic integration was developed and used to provide sufficiently low levels of systematic error along with high numerical efficiency and statistical stability. The calculated results are in excellent quantitative (rmsd = 1.0 kcal/mol) and qualitative (R2 = 0.90) agreement with experimental data. The potential of the methodology to explain the observed differences in the ligand affinities is also demonstrated.
关键词：molecular dynamics simulation ; serine protease ; drug design
