Structure-based maximal affinity model predicts small-molecule druggability

被引:522
作者
Cheng, Alan C.
Coleman, Ryan G.
Smyth, Kathleen T.
Cao, Qing
Soulard, Patricia
Caffrey, Daniel R.
Salzberg, Anna C.
Huang, Enoch S.
机构
[1] Amgen Inc, Cambridge, MA 02139 USA
[2] Pfizer Global Res & Dev, Res Technol Ctr, Dept Biol Sci, Cambridge, MA 02139 USA
[3] Pfizer Global Res & Dev, Res Technol Ctr, Dept Mol Informat, Cambridge, MA 02139 USA
关键词
D O I
10.1038/nbt1273
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Lead generation is a major hurdle in small-molecule drug discovery, with an estimated 60% of projects failing from lack of lead matter or difficulty in optimizing leads for drug-like properties. It would be valuable to identify these less-druggable targets before incurring substantial expenditure and effort. Here we show that a model-based approach using basic biophysical principles yields good prediction of druggability based solely on the crystal structure of the target binding site. We quantitatively estimate the maximal affinity achievable by a drug-like molecule, and we show that these calculated values correlate with drug discovery outcomes. We experimentally test two predictions using high-throughput screening of a diverse compound collection. The collective results highlight the utility of our approach as well as strategies for tackling difficult targets.
引用
收藏
页码:71 / 75
页数:5
相关论文
共 32 条
[1]   Small-molecule inhibitors of protein-protein interactions: Progressing towards the dream [J].
Arkin, MR ;
Wells, JA .
NATURE REVIEWS DRUG DISCOVERY, 2004, 3 (04) :301-317
[2]   Optimal charges in lead progression: A structure-based neuraminidase case study [J].
Armstrong, KA ;
Tidor, B ;
Cheng, AC .
JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (08) :2470-2477
[3]   Rediscovering the sweet spot in drug discovery [J].
Brown, D ;
Superti-Furga, G .
DRUG DISCOVERY TODAY, 2003, 8 (23) :1067-1077
[4]   Surface topography dependence of biomolecular hydrophobic hydration [J].
Cheng, YK ;
Rossky, PJ .
NATURE, 1998, 392 (6677) :696-699
[5]   HYDROPHOBIC BONDING AND ACCESSIBLE SURFACE-AREA IN PROTEINS [J].
CHOTHIA, C .
NATURE, 1974, 248 (5446) :338-339
[6]   An intuitive approach to measuring protein surface curvature [J].
Coleman, RG ;
Burr, MA ;
Souvaine, DL ;
Cheng, AC .
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2005, 61 (04) :1068-1074
[7]  
Davis AM, 1999, ANGEW CHEM INT EDIT, V38, P737, DOI 10.1002/(SICI)1521-3773(19990315)38:6<736::AID-ANIE736>3.0.CO
[8]  
2-R
[9]   The development of imatinib as a therapeutic agent for chronic myeloid leukemia [J].
Deininger, M ;
Buchdunger, E ;
Druker, BJ .
BLOOD, 2005, 105 (07) :2640-2653
[10]   PARTITIONING OF NONPOLAR SOLUTES INTO BILAYERS AND AMORPHOUS N-ALKANES [J].
DEYOUNG, LR ;
DILL, KA .
JOURNAL OF PHYSICAL CHEMISTRY, 1990, 94 (02) :801-809