Muegge Ingo
Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877-0368, USA.
J Med Chem. 2006 Oct 5;49(20):5895-902. doi: 10.1021/jm050038s.
Knowledge-based scoring functions have become accepted choices for fast scoring putative protein-ligand complexes according to their binding affinities. Since their introduction 5 years ago, the knowledge base of protein-ligand complexes has grown to the point were rederiving potentials of mean force becomes meaningful for statistical reasons. Revisiting potential of mean force (PMF) scoring (J. Med. Chem. 1999, 42, 791), we present an updated PMF04 scoring function that is based on 7152 protein-ligand complexes from the PDB. This constitutes an increase of about 10-fold compared to the knowledge base of the original PMF99 score (697 complexes). Because of the increased statistical basis of the PMF04 score, potentials for metal ions have been derived for the first time. In addition, potentials for halogens have reached statistical significance and are included also. Comparison of scoring accuracies between PMF99 and PMF04 shows an increased performance of the new score for many well-established test sets. Extending the testing of PMF scoring to the recently introduced PDBbind database containing the large number of 800 protein-ligand complexes illustrates the current limits of the approach.
基于知识的评分函数已成为根据结合亲和力快速评分假定蛋白质-配体复合物的公认选择。自5年前引入以来，蛋白质-配体复合物的知识库已发展到重新推导平均力势能因统计原因而变得有意义的程度。回顾平均力势能（PMF）评分（《药物化学杂志》1999年，42卷，791页），我们提出了一种更新的PMF04评分函数，该函数基于来自蛋白质数据银行（PDB）的7152个蛋白质-配体复合物。与原始PMF99评分（697个复合物）的知识库相比，这增加了约10倍。由于PMF04评分的统计基础增加，首次推导了金属离子的势能。此外，卤素的势能已达到统计显著性并也被纳入。PMF99和PMF04之间评分准确性的比较表明，对于许多成熟的测试集，新评分的性能有所提高。将PMF评分的测试扩展到最近引入的包含大量800个蛋白质-配体复合物的PDBbind数据库，说明了该方法当前的局限性。
