Can we discover pharmacological promiscuity early in the drug discovery process?

被引：64

作者：

Peters, Jens-Uwe ^{[1
]}

Hert, Jerome ^{[1
]}

Bissantz, Caterina ^{[1
]}

Hillebrecht, Alexander ^{[2
]}

Gerebtzoff, Gregori ^{[2
]}

Bendels, Stefanie ^{[2
]}

Tillier, Fabien ^{[3
]}

Migeon, Jacques ^{[4
]}

Fischer, Holger ^{[2
]}

Guba, Wolfgang ^{[1
]}

Kansy, Manfred ^{[2
]}

机构：

[1] F Hoffmann La Roche Ltd, pRED, Pharma Res & Early Dev, Discovery Chem, CH-4070 Basel, Switzerland

[2] F Hoffmann La Roche Ltd, pRED, Pharma Res & Early Dev, Nonclin Safety, CH-4070 Basel, Switzerland

[3] Cerep SA, Bois Eveque, F-86600 Celle Levescault, France

[4] Cerep Inc, Redmond, WA 98052 USA

来源：

DRUG DISCOVERY TODAY | 2012年 / 17卷 / 7-8期

关键词：

SAFETY PHARMACOLOGY; PHYSICOCHEMICAL PROPERTIES; PRIVILEGED STRUCTURES; MOLECULAR COMPLEXITY; RECEPTOR; DESIGN; LIPOPHILICITY; INHIBITORS; EFFICACY; BINDING;

D O I：

10.1016/j.drudis.2012.01.001

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The term 'pharmacological promiscuity' describes the activity of a single compound against multiple targets. When undesired, promiscuity is a major safety concern that needs to be detected as early as possible in the drug discovery process. The analysis of large datasets reveals that the majority of promiscuous compounds are characterized by recognizable molecular properties and structural motifs, the most important one being a basic center with a pK(a)(B) > 6. These compounds interact with a small set of targets such as aminergic GPCRs; some of these targets attract surprisingly high hit rates. In this review, we discuss current trends in the assessment of pharmacological promiscuity and propose strategies to enable early detection and mitigation.

引用

页码：325 / 335

页数：11

共 87 条

[1] 'Clean' or 'dirty' - Just how selective do drugs need to be? [J].

Abbenante, Giovanni ;

Reid, Robert C. ;

Fairlie, David P. .

AUSTRALIAN JOURNAL OF CHEMISTRY, 2008, 61 (09) :654-660

[2] Indene-based frameworks targeting the 5-HT6 serotonin receptor: Ring constraint in indenylsulfonamides using cyclic amines and structurally abbreviated counterparts [J].

Alcalde, Ermitas ;

Mesquida, Neus ;

Lopez-Perez, Sara ;

Frigola, Jordi ;

Merce, Ramon ;

Holenz, Joerg ;

Pujol, Marta ;

Hernandez, Enrique .

BIOORGANIC & MEDICINAL CHEMISTRY, 2009, 17 (20) :7387-7397

[3] THE FUTURE OF TOXICITY TESTING [J].

Andersen, Melvin E. ;

Al-Zoughool, Mustafa ;

Croteau, Maxine ;

Westphal, Margit ;

Krewski, Daniel .

JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART B-CRITICAL REVIEWS, 2010, 13 (2-4) :163-196

[4] MOLECULAR-CONFORMATION AND BIOLOGICAL-ACTIVITY OF CENTRAL NERVOUS-SYSTEM ACTIVE-DRUGS [J].

ANDREWS, PR ;

LLOYD, EJ .

MEDICINAL RESEARCH REVIEWS, 1982, 2 (04) :355-393

[5]

[Anonymous], 2008, C LOG P VAL WER CALC

[6] Kinase-likeness and kinase-privileged fragments: Toward virtual polypharmacology [J].

Aronov, Alex M. ;

McClain, Brian ;

Moody, Cameron Stuver ;

Murcko, Mark A. .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (05) :1214-1222

[7]

Azzaoui K, 2007, CHEMMEDCHEM, V2, P874, DOI 10.1002/cmdc.200700036

[8] Analysis of pharmacology data and the prediction of adverse drug reactions and off-target effects from chemical structure [J].

Bender, Andreas ;

Scheiber, Josef ;

Glick, Meir ;

Davies, John W. ;

Azzaoui, Kamal ;

Hamon, Jacques ;

Urban, Laszlo ;

Whitebread, Steven ;

Jenkins, Jeremy L. .

CHEMMEDCHEM, 2007, 2 (06) :861-873

[9] Chemical target and pathway toxicity mechanisms defined in primary human cell systems [J].

Berg, Ellen L. ;

Yang, Jian ;

Melrose, Jennifer ;

Nguyen, Dat ;

Privat, Sylvie ;

Rosler, Elen ;

Kunkel, Eric J. ;

Ekins, Sean .

JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS, 2010, 61 (01) :3-15

[10] Adverse drug reactions in United States hospitals [J].

Bond, CA ;

Raehl, CL .

PHARMACOTHERAPY, 2006, 26 (05) :601-608

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