Adding calorimetric data to decision making in lead discovery: a hot tip

被引：291

作者：

Ladbury, John E. ^{[1
]}

Klebe, Gerhard ^{[2
]}

Freire, Ernesto ^{[3
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[2] Univ Marburg, Inst Pharmazeut Chem, D-635032 Marburg, Germany

[3] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA

来源：

NATURE REVIEWS DRUG DISCOVERY | 2010年 / 9卷 / 01期

关键词：

ISOTHERMAL TITRATION CALORIMETRY; LIGAND EFFICIENCY; BINDING; AFFINITY; ENTHALPY; THROMBIN; OPTIMIZATION; INHIBITORS; PROTEINS; TRYPSIN;

D O I：

10.1038/nrd3054

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：

Recognition of the limitations of high-throughput screening approaches in the discovery of candidate drugs has reawakened interest in structure-based and other rational design methods. Here, we describe how isothermal titration calorimetry can be used to obtain thermodynamic data on the binding of compounds to protein targets. We propose that these data - particularly the change in enthalpy - could provide a valuable, complementary addition to established tools for selecting compounds in lead discovery and for aiding lead optimization.

引用

页码：23 / 27

页数：5

共 31 条

[1] Ligand efficiency indices as guideposts for drug discovery [J].

Abad-Zapatero, C ;

Metz, JT .

DRUG DISCOVERY TODAY, 2005, 10 (07) :464-469

[2] Evaluation of linked protonation effects in protein binding reactions using isothermal titration calorimetry [J].

Baker, BM ;

Murphy, KP .

BIOPHYSICAL JOURNAL, 1996, 71 (04) :2049-2055

[3] Protonation changes upon ligand binding to trypsin and thrombin: Structural interpretation based on pKa calculations and ITC experiments [J].

Czodrowski, Paul ;

Sotriffer, Christoph A. ;

Klebe, Gerhard .

JOURNAL OF MOLECULAR BIOLOGY, 2007, 367 (05) :1347-1356

[4] Application and limitations of X-ray crystallographic data in structure-based ligand and drug design [J].

Davis, AM ;

Teague, SJ ;

Kleywegt, GJ .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2003, 42 (24) :2718-2736

[5] Factorising ligand affinity:: A combined thermodynamic and crystallographic study of trypsin and thrombin inhibition [J].

Dullweber, F ;

Stubbs, MT ;

Musil, D ;

Stürzebecher, J ;

Klebe, G .

JOURNAL OF MOLECULAR BIOLOGY, 2001, 313 (03) :593-614

[6] Do enthalpy and entropy distinguish first in class from best in class? [J].

Freire, Ernesto .

DRUG DISCOVERY TODAY, 2008, 13 (19-20) :869-874

[7]

Freire Ernesto, 2005, V3, P291, DOI 10.1007/0-387-24532-4_13

[8] Thermodynamic inhibition profile of a cyclopentyl and a cyclohexyl derivative towards thrombin: The same but for different reasons [J].

Gerlach, Christof ;

Smolinski, Michael ;

Steuber, Holger ;

Sotriffer, Christoph A. ;

Heine, Andreas ;

Hangauer, David G. ;

Klebe, Gerhard .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2007, 46 (44) :8511-8514

[9] Molecular complexity and its impact on the probability of finding leads for drug discovery [J].

Hann, MM ;

Leach, AR ;

Harper, G .

JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES, 2001, 41 (03) :856-864

[10] Fragment-based lead discovery using X-ray crystallography [J].

Hartshorn, MJ ;

Murray, CW ;

Cleasby, A ;

Frederickson, M ;

Tickle, IJ ;

Jhoti, H .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (02) :403-413

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