Abstract
Author SummaryMany beneficial pharmacological interventions were first discovered by observing the effects of perturbation of intact biological systems by small organic molecules without a priori knowledge of their targets. This forward pharmacological approach has the advantage of directly identifying new pharmacological agents that are active on complex biological processes. However, because of experimental feasibility, systematic application of this approach is generally limited to small animals such as the roundworm C. elegans and zebrafish, raising the question of whether use of these animals could identify compounds that act on ortholgous mammalian targets. A significant challenge in addressing this question is the determination of the molecular identities of the compounds' targets responsible for the desired phenotypic outcomes. Here we describe a computational approach for target identification based on structural similarities of newly identified compounds to known ligand interactions with mostly mammalian targets. For several of the compounds emerging from a C. elegans phenotypic screen, we predict and confirm mammalian targets using in vitro binding assays. Using genetic and pharmacological assays, we then demonstrate that a subset of these compounds alter C. elegans feeding rates through the C. elegans counterparts of the predicted mammalian targets.
Highlights
Before the molecular biology era, pharmacological targets were typically classified by the effects of organic molecules on whole tissues [1]
Using statistical machinery similar to Basic Local Alignment Search Tool (BLAST), an expectation value (E-value) quantifies the possibility that observed structural similarities could occur by chance
As the identified targets are overwhelmingly mammalian, the ease of phenotypic screening strategies in C. elegans can be linked to identification of humanrelevant targets
Summary
Before the molecular biology era, pharmacological targets were typically classified by the effects of organic molecules on whole tissues [1]. Examples include the inference of the a- and b-adrenergic pathways in the 1940s [2], the inference of the H2 histaminergic receptor [3] and of the m, and k-opioid receptors in the 1970s [4], and the proposal of the 5-HT3 serotonergic receptor in the mid-1980s [5]. These targets were eventually characterized by molecular biology, the tissue and organism approach had the advantage that the compounds emerging from it were active on a physiologically intact tissue or organismal circuit, and directly linked functional perturbation of targets to biological effects. As a physiological process, feeding behavior is the
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