Reaching for high-hanging fruit in drug discovery at protein-protein interfaces

被引:1548
作者
Wells, James A.
McClendon, Christopher L.
机构
[1] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94156 USA
[2] Univ Calif San Francisco, Dept Mol & Cellular Pharmacol, San Francisco, CA 94156 USA
[3] Univ Calif San Francisco, Grad Grp Biophys, San Francisco, CA 94156 USA
关键词
D O I
10.1038/nature06526
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Targeting the interfaces between proteins has huge therapeutic potential, but discovering small- molecule drugs that disrupt protein - protein interactions is an enormous challenge. Several recent success stories, however, indicate that protein - protein interfaces might be more tractable than has been thought. These studies discovered small molecules that bind with drug- like potencies to 'hotspots' on the contact surfaces involved in protein - protein interactions. Remarkably, these small molecules bind deeper within the contact surface of the target protein, and bind with much higher efficiencies, than do the contact atoms of the natural protein partner. Some of these small molecules are now making their way through clinical trials, so this high-hanging fruit might not be far out of reach.
引用
收藏
页码:1001 / 1009
页数:9
相关论文
共 99 条
  • [1] The X-ray structure of the papillomavirus helicase in complex with its molecular matchmaker E2
    Abbate, EA
    Berger, JM
    Botchan, MR
    [J]. GENES & DEVELOPMENT, 2004, 18 (16) : 1981 - 1996
  • [2] The Bcl-2 protein family: Arbiters of cell survival
    Adams, JM
    Cory, S
    [J]. SCIENCE, 1998, 281 (5381) : 1322 - 1326
  • [3] SPACE-FILLING MODELS OF KINASE CLEFTS AND CONFORMATION CHANGES
    ANDERSON, CM
    ZUCKER, FH
    STEITZ, TA
    [J]. SCIENCE, 1979, 204 (4391) : 375 - 380
  • [4] Protein-protein interactions and cancer: small molecules going in for the kill
    Arkin, M
    [J]. CURRENT OPINION IN CHEMICAL BIOLOGY, 2005, 9 (03) : 317 - 324
  • [5] Small-molecule inhibitors of protein-protein interactions: Progressing towards the dream
    Arkin, MR
    Wells, JA
    [J]. NATURE REVIEWS DRUG DISCOVERY, 2004, 3 (04) : 301 - 317
  • [6] Binding of small molecules to an adaptive protein-protein interface
    Arkin, MR
    Randal, M
    DeLano, WL
    Hyde, J
    Luong, TN
    Oslob, JD
    Raphael, DR
    Taylor, L
    Wang, J
    McDowell, RS
    Wells, JA
    Braisted, AC
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (04) : 1603 - 1608
  • [7] Discovery of a potent small molecule IL-2 inhibitor through fragment assembly
    Braisted, AC
    Oslob, JD
    Delano, WL
    Hyde, J
    McDowell, RS
    Waal, N
    Yu, C
    Arkin, MR
    Raimundo, BC
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2003, 125 (13) : 3714 - 3715
  • [8] Effects of conformational dynamics on predicted protein druggability
    Brown, Scott P.
    Hajduk, Philip J.
    [J]. CHEMMEDCHEM, 2006, 1 (01) : 70 - +
  • [9] Studies leading to potent, dual inhibitors of bcl-2 and Bcl-xL
    Bruncko, Milan
    Oost, Thorsten K.
    Belli, Barbara A.
    Ding, Hong
    Joseph, Mary K.
    Kunzer, Aaron
    Martineau, Darlene
    McClellan, William J.
    Mitten, Michael
    ng, Shi-Chu Ng
    Nimmer, Paul M.
    Oltersdorf, Tilman
    Park, Cheol-Min
    Petros, Andrew M.
    Shoemaker, Alexander R.
    Song, Xiaohong
    Wang, Xilu
    Wendt, Michael D.
    Zhang, Haichao
    Fesik, Stephen W.
    Rosenberg, Saul H.
    Elmore, Steven W.
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (04) : 641 - 662
  • [10] Fragment-based lead discovery: leads by design
    Carr, RAE
    Congreve, M
    Murray, CW
    Rees, DC
    [J]. DRUG DISCOVERY TODAY, 2005, 10 (14) : 987 - 992