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 while 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 collection for screening. Rational methods for selecting diverse chemical libraries are essential for their effective use in high-throughput screens.

Figure 1. Chemical structures used in compound filtering

Chemical structures of functional groups commonly used to remove compounds from consideration in HTS assays. The functional group name and SMILES/SMARTS string used in the filter are reported.

Figure 2. Example of similarity between compounds

Four compounds and the Tanimoto similarity between them. The compounds were assigned radial fingerprints using Schrodinger’s Canvas software at 64-bit precision using daylight invariant atom types.

Figure 3. Clustering of compounds in chemical space

A two dimensional representation of chemical space being partitioned into clusters of similar compounds using a simple sphere exclusion method.