| RRC ID |
46060
|
| 著者 |
Lemieux GA, Keiser MJ, Sassano MF, Laggner C, Mayer F, Bainton RJ, Werb Z, Roth BL, Shoichet BK, Ashrafi K.
|
| タイトル |
In silico molecular comparisons of C. elegans and mammalian pharmacology identify distinct targets that regulate feeding.
|
| ジャーナル |
PLoS Biol
|
| Abstract |
Phenotypic screens can identify molecules that are at once penetrant and active on the integrated circuitry of a whole cell or organism. These advantages are offset by the need to identify the targets underlying the phenotypes. Additionally, logistical considerations limit screening for certain physiological and behavioral phenotypes to organisms such as zebrafish and C. elegans. This further raises the challenge of elucidating whether compound-target relationships found in model organisms are preserved in humans. To address these challenges we searched for compounds that affect feeding behavior in C. elegans and sought to identify their molecular mechanisms of action. Here, we applied predictive chemoinformatics to small molecules previously identified in a C. elegans phenotypic screen likely to be enriched for feeding regulatory compounds. Based on the predictions, 16 of these compounds were tested in vitro against 20 mammalian targets. Of these, nine were active, with affinities ranging from 9 nM to 10 µM. Four of these nine compounds were found to alter feeding. We then verified the in vitro findings in vivo through genetic knockdowns, the use of previously characterized compounds with high affinity for the four targets, and chemical genetic epistasis, which is the effect of combined chemical and genetic perturbations on a phenotype relative to that of each perturbation in isolation. Our findings reveal four previously unrecognized pathways that regulate feeding in C. elegans with strong parallels in mammals. Together, our study addresses three inherent challenges in phenotypic screening: the identification of the molecular targets from a phenotypic screen, the confirmation of the in vivo relevance of these targets, and the evolutionary conservation and relevance of these targets to their human orthologs.
|
| 巻・号 |
11(11)
|
| ページ |
e1001712
|
| 公開日 |
2013-11-1
|
| DOI |
10.1371/journal.pbio.1001712
|
| PII |
PBIOLOGY-D-13-01770
|
| PMID |
24260022
|
| PMC |
PMC3833878
|
| MeSH |
Animals
Caenorhabditis elegans / drug effects*
Caenorhabditis elegans / physiology
Caenorhabditis elegans Proteins / antagonists & inhibitors
Caenorhabditis elegans Proteins / metabolism
Computer Simulation
Drug Evaluation, Preclinical
Feeding Behavior / drug effects*
Humans
Peristalsis / drug effects
Pharynx / drug effects
Phenotype
Quinolines / pharmacology
Receptors, G-Protein-Coupled / antagonists & inhibitors
Receptors, G-Protein-Coupled / metabolism
Small Molecule Libraries
|
| IF |
7.076
|
| 引用数 |
14
|
|
WOS 分野
|
BIOLOGY
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| 線虫 |
tm4867
tm4152
tm1811
tm355 |
