Dark chemical matter as a promising starting point for drug lead discovery

被引：101

作者：

Wassermann, Anne Mai ^{[1
]}

Lounkine, Eugen ^{[1
]}

Hoepfner, Dominic ^{[2
]}

Le Goff, Gaelle ^{[1
]}

King, Frederick J. ^{[1
,3
]}

Studer, Christian ^{[2
]}

Peltier, John M. ^{[1
]}

Grippo, Melissa L. ^{[1
]}

Prindle, Vivian ^{[3
]}

Tao, Jianshi ^{[3
]}

Schuffenhauer, Ansgar ^{[2
]}

Wallace, Iain M. ^{[1
]}

Chen, Shanni ^{[1
]}

Krastel, Philipp ^{[2
]}

Cobos-Correa, Amanda ^{[2
]}

Parker, Christian N. ^{[2
]}

Davies, John W. ^{[1
]}

Glick, Meir ^{[1
]}

机构：

[1] Novartis Inst BioMed Res Inc, Cambridge, MA USA

[2] Novartis Inst BioMed Res Inc, Basel, Switzerland

[3] Novartis Res Fdn, Genom Inst, San Diego, CA USA

来源：

NATURE CHEMICAL BIOLOGY | 2015年 / 11卷 / 12期

关键词：

SMALL MOLECULES; GENE; PROMISCUITY; DIVERSITY; LIBRARIES; CLIFFS;

D O I：

10.1038/nchembio.1936

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

High-throughput screening (HTS) is an integral part of early drug discovery. Herein, we focused on those small molecules in a screening collection that have never shown biological activity despite having been exhaustively tested in HTS assays. These compounds are referred to as 'dark chemical matter' (DCM). We quantified DCM, validated it in quality control experiments, described its physicochemical properties and mapped it into chemical space. Through analysis of prospective reporter-gene assay, gene expression and yeast chemogenomics experiments, we evaluated the potential of DCM to show biological activity in future screens. We demonstrated that, despite the apparent lack of activity, occasionally these compounds can result in potent hits with unique activity and clean safety profiles, which makes them valuable starting points for lead optimization efforts. Among the identified DCM hits was a new antifungal chemotype with strong activity against the pathogen Cryptococcus neoformans but little activity at targets relevant to human safety.

引用

页码：958 / 966

页数：9

共 33 条

[1] NIH Molecular Libraries Initiative [J].