The role of ligand efficiency metrics in drug discovery

被引：899

作者：

Hopkins, Andrew L. ^{[1
]}

Keserue, Gyoergy M. ^{[2
]}

Leeson, Paul D. ^{[3
]}

Rees, David C. ^{[4
]}

Reynolds, Charles H. ^{[5
]}

机构：

[1] Univ Dundee, Coll Life Sci, Div Biol Chem & Drug Discovery, Dundee DD1 5EH, Scotland

[2] Hungarian Acad Sci, Res Ctr Nat Sci, H-1525 Budapest, Hungary

[3] GlaxoSmithKline, Med Res Ctr, Stevenage SG1 2NY, Herts, England

[4] Astex Pharmaceut, Cambridge CB4 0QA, England

[5] Gfree Bio, Doylestown, PA 18902 USA

来源：

NATURE REVIEWS DRUG DISCOVERY | 2014年 / 13卷 / 02期

关键词：

ACTIVE CCR5 ANTAGONIST; MARKETED ORAL-DRUGS; MEDICINAL CHEMISTRY; LIPOPHILIC EFFICIENCY; MOLECULAR-PROPERTIES; CETP INHIBITORS; LEAD DISCOVERY; PHYSICOCHEMICAL PROPERTIES; SELECTIVE INHIBITOR; PROPERTY PROFILES;

D O I：

10.1038/nrd4163

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 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

The judicious application of ligand or binding efficiency metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimized ligand efficiency values for their targets. Optimizing ligand efficiency metrics based on both molecular mass and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the inflation of these properties that has been observed in current medicinal chemistry practice, and to increase the quality of drug candidates.

引用

页码：105 / 121

页数：17

共 86 条

[1]

Ligand efficiency indices for effective drug discovery [J].

Abad-Zapatero, Cele .

EXPERT OPINION ON DRUG DISCOVERY, 2007, 2 (04) :469-488

[2]

FUNCTIONAL-GROUP CONTRIBUTIONS TO DRUG RECEPTOR INTERACTIONS [J].

ANDREWS, PR ;

CRAIK, DJ ;

MARTIN, JL .

JOURNAL OF MEDICINAL CHEMISTRY, 1984, 27 (12) :1648-1657

[3]

Fragment-based lead discovery grows up [J].

Baker, Monya .

NATURE REVIEWS DRUG DISCOVERY, 2013, 12 (01) :5-10

[4]

Bickerton GR, 2012, NAT CHEM, V4, P90, DOI [10.1038/NCHEM.1243, 10.1038/nchem.1243]

[5]

Blake JF, 2003, BIOTECHNIQUES, P16

[6]

New molecular insights into CETP structure and function: a review [J].

Charles, M. Arthur ;

Kane, John P. .

JOURNAL OF LIPID RESEARCH, 2012, 53 (08) :1451-1458

[7]

Balancing hERG affinity and absorption in the discovery of AZD5672, an orally active CCR5 antagonist for the treatment of rheumatoid arthritis [J].

Cumming, John G. ;

Tucker, Howard ;

Oldfield, John ;

Fielding, Colin ;

Highton, Adrian ;

Faull, Alan ;

Wild, Martin ;

Brown, Dearg ;

Wells, Stuart ;

Shaw, John .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (04) :1655-1659

[8]

Design and Synthesis of Diazatricyclodecane Agonists of the G-Protein-Coupled Receptor 119 [J].

Darout, Etzer ;

Robinson, Ralph P. ;

McClure, Kim F. ;

Corbett, Matthew ;

Li, Bryan ;

Shavnya, Andrei ;

Andrews, Melissa P. ;

Jones, Christopher S. ;

Li, Qifang ;

Minich, Martha L. ;

Mascitti, Vincent ;

Guimaraes, Cristiano R. W. ;

Munchhof, Michael J. ;

Bahnck, Kevin B. ;

Cai, Cuiman ;

Price, David A. ;

Liras, Spiros ;

Bonin, Paul D. ;

Cornelius, Peter ;

Wang, Ruduan ;

Bagdasarian, Victoria ;

Sobota, Colleen P. ;

Hornby, Sam ;

Masterson, Victoria M. ;

Joseph, Reena M. ;

Kalgutkar, Amit S. ;

Chen, Yue .

JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (01) :301-319

[9]

Comprehensive analysis of kinase inhibitor selectivity [J].

Davis, Mindy I. ;

Hunt, Jeremy P. ;

Herrgard, Sanna ;

Ciceri, Pietro ;

Wodicka, Lisa M. ;

Pallares, Gabriel ;

Hocker, Michael ;

Treiber, Daniel K. ;

Zarrinkar, Patrick P. .

NATURE BIOTECHNOLOGY, 2011, 29 (11) :1046-U124

[10]

Medicinal chemistry of Hsp90 inhibitors [J].

Drysdale, Martin J. ;

Brough, Paul A. .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2008, 8 (10) :859-868

← 1 2 3 4 5 6 7 8 9 →