Small-Molecule Library Subset Screening as an Aid for Accelerating Lead Identification

Abstract

Several small-compound library subsets (14,000 to 56,000) have been established to complement screening of a larger Genentech corporate library (~1,300,000). Two validation sets (~1% of the total library) containing compounds representative of the main library were chosen by selection of plates or individual compounds. Use of these subsets guided selection of assay configuration, validated assay reproducibility, and provided estimates of hit rates expected from our full library. A larger diversity subset representing the scaffold diversity of the full library (3.4% of the total) was designed for screening more challenging targets with limited reagent availability or low-throughput assays. Retrospective analysis of this subset showed hit rates similar to those of the main library while recovering a higher proportion of hit scaffolds. Finally, a property-restricted diversity set called the "in-between library" was established to identify ligand-efficient compounds of molecular size between those typically found in fragment and high-throughput screening libraries. It was screened at fivefold higher concentrations than the main library to facilitate identification of less potent yet ligand-efficient compounds. Taken together, this work underscores the value of generating multiple purpose-focused, diversity-based library subsets that are designed using computational approaches coupled with internal screening data analyses to accelerate the lead discovery process.

Nanomolar Synthesis in Droplet Microarrays with UV‐Triggered On‐Chip Cell Screening

“…When the spot is filled with 5 µL of solvent, this leads to a maximum accessible concentration of 954 × 10 −6 m . According to the literature, the recommended concentration for high‐throughput hit discovery is 1–10 × 10 −6 m , showing that the amount of compound in each spot is enough for biological screenings even in cases of yields less than 100%. The nanoporous HEMA‐ co ‐EDMA polymer is opaque when it is dry, but turns transparent when wetted in the HL spots due to the reduction of light scattering.…”

chemalot and chemalot_knime: Command line programs as workflow tools for drug discovery

“…All small molecule structures with less than 2 Å resolution were exported from the in-house copy of the PDB database stored in PROASIS [47] using sdfExport. The structures were filtered by molecular weight (<500) and number of rotatable bonds (<7) and by removing structures that did not pass our compound screening filters [48]. Finally known metal counter-ions were removed with sdwash [49].…”

High throughput screening identifies novel, cell cycle‐arresting small molecule enhancers of transient protein expression

“…10 lM is typically the maximum recommended concentration for SM HTS 34 and is consistent with previously reported screening concentrations for the Genentech library. 35 A 10 lM was chosen to elicit strong inhibition or activation of cellular pathways, which might be beneficial for transient productivity.…”