Title:Strategies for Small Molecule Library Design
Volume: 20
Issue: 20
Author(s): David W. Sheppard, Michael J. Lipkin, C. John Harris, Cornel Catana and Pieter F.W. Stouten
Affiliation:
Keywords:
Library design, target focus, diversity, kinase, ion channel, GPCR, PPI, epigenetics, ubiquitin proteasome pathway, HTS, hit rate,
BioFocus, Galapagos, SoftFocus, FieldFocus.
Abstract: Compilation of an appropriate set of compounds is essential for the success of a small molecule screen. When very little is
known about the target and when no or few ligands have been identified, the screening file is often made as diverse as possible. When
structural information on the target or target family is available or ligands of the target are known, it is more efficient to apply a ligand- or
target-focused bias, so as to predominantly screen compounds that can be expected to modulate the target. One way to achieve this is to
select subsets of existing collections; another is to specifically design and synthesize libraries focused on a particular target, target family
or mechanism of action. Despite the number of success stories, designing such libraries is still challenging and requires specialized
knowledge, especially in emerging target areas such as protein-protein interactions (PPI), epigenetics and the ubiquitin proteasome pathway.
BioFocus has successfully produced so-called SoftFocus® libraries for many years, evolving their targets from kinases to GPCRs
and ion channels to difficult targets in the epigenetics and PPI fields. This article outlines several of the principles applied to SoftFocus
library design, showcasing successes achieved by BioFocus’ clients. In addition, screening results for a comprehensive set of BioFocus’
kinase libraries against 20 kinase targets are used to demonstrate the power of the SoftFocus approach in delivering both selective and
less-selective compounds and libraries against these targets.
Trademarks: BioFocus®, SoftFocus®, HDRA™, FieldFocus™, Thematic Analysis™, ThemePair™ and ThemePair Fragment™ are trademarks
of Galapagos NV and/or its affiliates.
