Combined Analysis of Phenotypic and Target-Based Screening in Assay Networks

Abstract

Small-molecule screens are an integral part of drug discovery. Public domain data in PubChem alone represent more than 158 million measurements, 1.2 million molecules, and 4300 assays. We conducted a global analysis of these data, building a network of assays and connecting the assays if they shared nonpromiscuous active molecules. This network spans both phenotypic and target-based screens, recapitulates known biology, and identifies new polypharmacology. Phenotypic screens are extremely important for drug discovery, contributing to the discovery of a large proportion of new drugs. Connections between phenotypic and biochemical, target-based screens can suggest strategies for repurposing both small-molecule and biologic drugs. For example, a screen for molecules that prevent cell death from a mutated version of superoxide-dismutase is linked with ALOX15. This connection suggests a therapeutic role for ALOX15 inhibitors in amyotrophic lateral sclerosis. An interactive version of the network is available online (http://swami.wustl.edu/flow/assay_network.html).

Identification of Steroidogenic Components Derived From Gardenia jasminoides Ellis Potentially Useful for Treating Postmenopausal Syndrome

“…With the combination of the major compounds from the active fraction and possible active ingredients from network pharmacology, phenotypic (estrogen-stimulating effect) and target-based (aromatase/FSHR/StAR/ERα/ERβ) methods were used to find the active components of GJE (Lu et al, 2016 ). Phenotypic approaches play a crucial role in drug discovery because data from the large-scale drug screening and target-based approaches suggest the relationships between a potential new drug and its molecular targets (Gilbert, 2013 ; Swamidass et al, 2014 ). Finally, the bioactive compounds of GJE that could stimulate the biosynthesis of ovarian estradiol was reported (Figure 1 ).…”

Benchmarking Data Sets from PubChem BioAssay Data: Current Scenario and Room for Improvement

“…Upon acquiring experimental input from the resource, scientists may use it in various ways to achieve their research objectives. Several review articles have been published in this regard [ 7 , 40 , 41 ], summarizing a wide range of studies that were conducted on the basis of PubChem BioAssay data [ 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ]. In this section, we only place our focus on the research featuring benchmarking data collections that were constructed by the cheminformatics community from PubChem’s experimental results as a means of validating in silico screening protocols.…”

Getting the most out of PubChem for virtual screening

“…An alternative network-based approach has also been developed which allows for analysis of both target-based and phenotypic assays. In a study by Swamidass et al ., 109 a network of 1,581 assays with at least 5,000 tested compounds was constructed based on similarity between two assays in terms of correlation between bioactivity scores of the compounds tested in both assays. The bioactivity score correlation was quantified with the promiscuity-adjusted correlation (PAC), which downweighs promiscuous compounds that were tested active in many assays.…”