Evidence-Based and Quantitative Prioritization of Tool Compounds in Phenotypic Drug Discovery

Abstract

The use of potent and selective chemical tools with well-defined targets can help elucidate biological processes driving phenotypes in phenotypic screens. However, identification of selective compounds en masse to create targeted screening sets is non-trivial. A systematic approach is needed to prioritize probes, which prevents the repeated use of published but unselective compounds. Here we performed a meta-analysis of integrated large-scale, heterogeneous bioactivity data to create an evidence-based, quantitative metric to systematically rank tool compounds for targets. Our tool score (TS) was then tested on hundreds of compounds by assessing their activity profiles in a panel of 41 cell-based pathway assays. We demonstrate that high-TS tools show more reliably selective phenotypic profiles than lower-TS compounds. Additionally we highlight frequently tested compounds that are non-selective tools and distinguish target family polypharmacology from cross-family promiscuity. TS can therefore be used to prioritize compounds from heterogeneous databases for phenotypic screening.

Systematic Chemogenetic Library Assembly

“…Having constructed a large-scaled integrated bioactivity data warehouse, we next devised a computational model for prioritization of MoA Box members through a quantitative confidence metric, which we later developed into a Tool Score. 10,11 In brief, a Tool Score evaluates both the strength of evidence of compound-target modulation and target selectivity. Strength of evidence derives from combining multiple computational inferences or annotations into a strength assertion.…”

Chemistry-based molecular signature underlying the atypia of clozapine

“…10, 11, 12, 13, 14, 15, 16, 17, 18, 26, 27 These studies demonstrate that polypharmacologic understanding of drug action (that is, based on the full set of relevant targets) is superior to the single-target view. However, drug action is incontrovertibly the product of both direct chemical activity against targets and the expression pattern of those targets in specific tissues in the human body.…”

“…In vivo , polypharmacologic views of the actions of these drugs have not been extensively proposed. Such views would consist of weighted ensembles of all the receptors expressed by the human genome and affected by specific drugs, 10, 11, 12, 13, 14, 15, 16, 17, 18 further stratified by the differential anatomic expression of these receptors.…”

Evidence-Based Precision Oncology with the Cancer Targetome

“…This presents its own challenge, as the choice of an appropriate activity threshold depends on the biological context of the problem. For determining bioactivity of compounds, the threshold of 10,000nM (10μM) is often used, but a much stricter threshold of 100nM or under is more appropriate when requiring interactions to be relevant to drug binding [31,53]. Paolini et al .…”