Compound Prioritization in Single-Concentration Screening Data Using Ligand Efficiency Indexes

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.