Physics-based scoring of protein-ligand complexes: Enrichment of known inhibitors in large-scale virtual screening

被引:135
作者
Huang, N [1 ]
Kalyanaraman, C [1 ]
Irwin, JJ [1 ]
Jacobson, MP [1 ]
机构
[1] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA
关键词
D O I
10.1021/ci0502855
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
We demonstrate that using an all-atom molecular mechanics force field combined with an implicit solvent model for scoring protein-ligand complexes is a promising approach for improving inhibitor enrichment ill the virtual screening of large compound databases. The rescoring method is evaluated by the extent to which known binders for nine diverse, therapeutically relevant enzymes are enriched against a background of similar to 100 000 drug-like decoys. The improvement in enrichment is most robust and dramatic within the top 1% of the ranked database, that is, the first thousand compounds; below the first few percent of the ranked database, there is little overall improvement. The improved early enrichment is likely due to the more realistic treatment of ligand and receptor desolvation in the rescoring procedure. We also present anecdotal but encouraging results assessing the ability of the rescoring method to predict specificity of inhibitors for structurally related proteins.
引用
收藏
页码:243 / 253
页数:11
相关论文
共 74 条
  • [51] A detailed comparison of current docking and scoring methods on systems of pharmaceutical relevance
    Perola, E
    Walters, WP
    Charifson, PS
    [J]. PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2004, 56 (02) : 235 - 249
  • [52] Structure-based discovery of a novel, noncovalent inhibitor of AmpC β-lactamase
    Powers, RA
    Morandi, F
    Shoichet, BK
    [J]. STRUCTURE, 2002, 10 (07) : 1013 - 1023
  • [53] A fast flexible docking method using an incremental construction algorithm
    Rarey, M
    Kramer, B
    Lengauer, T
    Klebe, G
    [J]. JOURNAL OF MOLECULAR BIOLOGY, 1996, 261 (03) : 470 - 489
  • [54] Nuclear hormone receptor targeted virtual screening
    Schapira, M
    Abagyan, R
    Totrov, M
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (14) : 3045 - 3059
  • [55] *SCHR INC, IMPACT V 2 7
  • [56] MATCHING CHEMISTRY AND SHAPE IN MOLECULAR DOCKING
    SHOICHET, BK
    KUNTZ, ID
    [J]. PROTEIN ENGINEERING, 1993, 6 (07): : 723 - 732
  • [57] Virtual screening of chemical libraries
    Shoichet, BK
    [J]. NATURE, 2004, 432 (7019) : 862 - 865
  • [58] Lead discovery using molecular docking
    Shoichet, BK
    McGovern, SL
    Wei, BQ
    Irwin, JJ
    [J]. CURRENT OPINION IN CHEMICAL BIOLOGY, 2002, 6 (04) : 439 - 446
  • [59] STRUCTURE-BASED DISCOVERY OF INHIBITORS OF THYMIDYLATE SYNTHASE
    SHOICHET, BK
    STROUD, RM
    SANTI, DV
    KUNTZ, ID
    PERRY, KM
    [J]. SCIENCE, 1993, 259 (5100) : 1445 - 1450
  • [60] Detailed analysis of scoring functions for virtual screening
    Stahl, M
    Rarey, M
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (07) : 1035 - 1042