title: Dark chemical matter as a promising starting point for drug lead discovery.
abstract: 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.
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Cambridge, Massachusetts, USA.
authors.forename: Anne Mai
authors.initials: AM
authors.lastname: Wassermann
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Cambridge, Massachusetts, USA.
authors.forename: Eugen
authors.initials: E
authors.lastname: Lounkine
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Basel, Switzerland.
authors.forename: Dominic
authors.initials: D
authors.lastname: Hoepfner
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Cambridge, Massachusetts, USA.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Le Goff
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Cambridge, Massachusetts, USA.|The Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: King
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Studer
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Cambridge, Massachusetts, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Peltier
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Cambridge, Massachusetts, USA.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Grippo
authors.affiliation: The Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Prindle
authors.affiliation: The Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
authors.forename: Jianshi
authors.initials: J
authors.lastname: Tao
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Basel, Switzerland.
authors.forename: Ansgar
authors.initials: A
authors.lastname: Schuffenhauer
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Cambridge, Massachusetts, USA.
authors.forename: Iain M
authors.initials: IM
authors.lastname: Wallace
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Cambridge, Massachusetts, USA.
authors.forename: Shanni
authors.initials: S
authors.lastname: Chen
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Basel, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Krastel
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Basel, Switzerland.
authors.forename: Amanda
authors.initials: A
authors.lastname: Cobos-Correa
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Basel, Switzerland.
authors.forename: Christian N
authors.initials: CN
authors.lastname: Parker
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Cambridge, Massachusetts, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Davies
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Cambridge, Massachusetts, USA.
authors.forename: Meir
authors.initials: M
authors.lastname: Glick
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D003455:Cryptococcus neoformans / Q000187:drug effects*; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents