title: Compound Prioritization in Single-Concentration Screening Data Using Ligand Efficiency Indexes.
abstract: The triage of compounds at the single-concentration screening phase of high-throughput screening (HTS) requires multiobjective optimization in order to achieve the best selection of hits, both in terms of potency and physicochemical properties, for a given number of compounds to test. In this regard, ligand efficiency indexes, well established as guides for hit prioritization in the dose-response phase of HTS, are less studied in the single-concentration phase. In the present work the use of ligand efficiency indexes in the prioritization of compounds in single-concentration is investigated. Formulas for deriving them from single-concentration screening data are provided. The statistical association between the single-concentration and dose-response ligand efficiency indexes is evaluated with a wide historical data set including multiple screens of different target classes and screening technologies. The results show Pearson's correlation coefficients r above 0.9 for compounds with dose-response curves, and areas under the curve (AUC) of receiver operating characteristic (ROC) curves above 0.85 after including compounds with no dose-response curves. This good statistical association contains the contribution of both the physicochemical parameter(s) in the ligand efficiency indexes, as well as the biological activity, as demonstrated by permutation tests. The "cost/benefit" of using different thresholds of single-concentration ligand efficiency indexes in rescuing different numbers of efficient compounds is systematically investigated, and cost/benefit curves are provided. Approximate thresholds are proposed for the different ligand efficiency parameters that results in large percentages of efficient compounds rescued while attempting to reduce the cost of compounds to test in dose-response mode. Finally, a practical example of implementation of these indexes that considers clustering of compounds is described, where the rescue of efficient compounds is higher and with a much lower cost than a typical response-driven selection.
authors: Department of Computational Chemistry, Centro de Investigación Básica, GSK, Parque Tecnológico de Madrid , Tres Cantos 28760, Spain.
authors: Gonzalo
authors: G
authors: Colmenarejo
mesh_terms: D003362:Cost-Benefit Analysis; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000191:economics / Q000379:methods*; D020128:Inhibitory Concentration 50; D008024:Ligands
chemical_list: D008024:Ligands