Rational Methods for the Selection of Diverse Screening Compounds

Abstract

Traditionally a pursuit of large pharmaceutical companies, high-throughput screening assays are becoming increasingly common within academic and government laboratories. This shift has been instrumental in enabling projects that have not been commercially viable, such as chemical probe discovery and screening against high risk targets. Once an assay has been prepared and validated, it must be fed with screening compounds. Crafting a successful collection of small molecules for screening poses a significant challenge. An optimized collection will minimize false positives whilst maximizing hit rates of compounds that are amenable to lead generation and optimization. Without due consideration of the relevant protein targets and the downstream screening assays, compound filtering and selection can fail to explore the great extent of chemical diversity and eschew valuable novelty. Herein, we discuss the different factors to be considered and methods that may be employed when assembling a structurally diverse compound screening collection. Rational methods for selecting diverse chemical libraries are essential for their effective use in high-throughput screens. Keywords Drug-like Molecule:A molecule with molecular properties that overlap with the majority of existing drugs.; High-throughput Screening: A screening process that utilises robotics and rapid data processing to perform millions of assays in a short space of time.; Molecular Similarity: A measure of the relatedness of two molecules. This would ideally quantify the similarity in biological effect but in practice tends to quantify the similarity in structure.; Molecular Diversity: A measure of how well a subset of molecules represents a larger set of molecules. A more diverse subset will tend to have a lower molecular similarity between molecules.; Frequent Hitter: A molecule or molecular substructure that hits numerous screening assays on different drug targets with a mode of action that is assumed to be non-specific.; Substructure Filter: A computational filter used to remove molecules containing molecular substructures that are considered to give rise to non-specific binding or deleterious pharmacodynamic properties.

A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products

“…As expected, these minor structural changes afford higher similarity scores (average of 0.67, see Supplementary Figure 2), consistent with work of others using Tanimoto coefficients. 48 For the similarity matrix of the full 49 compound set, please see Supplementary Figure 3.…”

Design of a General‐Purpose European Compound Screening Library for EU‐OPENSCREEN

“…There are basically two distinct, arguably equally valid approaches to diversity selection 50. 51 The first are so‐called pro‐rata methods, aimed at reproducing a core of the initial library by sampling, out of each CS zone, a number of compounds proportional to the local compound density. Alternatively, one may adopt homogeneity‐oriented approaches aimed at producing equal samples of every populated CS zone.…”

Development and Implementation of a High-Throughput High-Content Screening Assay to Identify Inhibitors of Androgen Receptor Nuclear Localization in Castration-Resistant Prostate Cancer Cells

“…To further prioritize the remaining hits, we classified and clustered their chemical structures, applied computational filters (PAINS/REOS) to identify and eliminate nuisance compounds and to predict their drug-like characteristics and potentially adverse ADME/Tox properties, 37,38 and considered their chemical tractability. A total of 23 small-molecule candidates were selected for further analysis.…”