Selecting, Acquiring, and Using Small Molecule Libraries for High‐Throughput Screening

Abstract

The selection, acquisition, and use of high‐quality small molecule libraries for screening is an essential aspect of drug discovery and chemical biology programs. Screening libraries continue to evolve as researchers gain a greater appreciation of the suitability of small molecules for specific biological targets, processes, and environments. The decision surrounding the makeup of any given small molecule library is informed by a multitude of variables, and opinions vary on best practices. The fitness of any collection relies upon upfront filtering to avoid problematic compounds, assess appropriate physicochemical properties, install the ideal level of structural uniqueness, and determine the desired extent of molecular complexity. These criteria are under constant evaluation and revision as academic and industrial organizations seek out collections that yield ever‐improving results from their screening portfolios. Practical questions including cost, compound management, screening sophistication, and assay objective also play a significant role in the choice of library composition. This overview attempts to offer advice to all organizations engaged in small molecule screening based upon current best practices and theoretical considerations in library selection and acquisition. Curr. Protoc. Chem. Biol. 4:177‐191 © 2012 by John Wiley & Sons, Inc.

Discovery of Key Physicochemical, Structural, and Spatial Properties of RNA‐Targeted Bioactive Ligands

“…Together, these differences support the existence of a “privileged chemical space” for RNA targeting and suggest several important future directions, including the explicit testing of these guiding principles against several RNA targets and the expansion of the properties analyzed. Methods including machine-based learning [24] and multi-parameter optimization [25] will be explored to design and create libraries [26] for efficient RNA-focused screening. We expect that our analysis will serve as a stepping stone to facilitate the discovery of chemical probes for RNAs and ultimately facilitate the discovery of small molecule drugs with novel modes of action against humankind’s most challenging diseases.…”

Cell-Based Screening to Identify Cytoprotective Compounds

“…Depending on the disease and target tissue, it might be possible to exclude certain chemistries and by using chemoinformatics filtering methods, the composition of the library might be limited to a set that is easier to handle [43]. A key concept is druglikeness, prediction of the properties of a molecule based on the physicochemical properties of approved drugs and filtering the compound library according to these parameters [44].…”

In‐house chemical library repurposing: A case example for Pseudomonas aeruginosa antibiofilm activity and quorum sensing inhibition

“…Chemists, including those not involved in drug discovery program, all around the globe develop hundreds of new compounds every day either to demonstrate new synthesis method or molecule. However, not all these compounds show the intended activity and the negative ones are shelved in the lab with no immediate use (Dandapani, Rosse, Southall, Salvino, & Thomas, ). We in this project take them to the next level of utility, where previously synthesized molecules kept in the lab are subjected to high through put analysis for antibiofilm activity.…”