Abstract
Target-focused compound libraries are collections of compounds which are designed to interact with an individual protein target or, frequently, a family of related targets (such as kinases, voltage-gated ion channels, serine/cysteine proteases). They are used for screening against therapeutic targets in order to find hit compounds that might be further developed into drugs. The design of such libraries generally utilizes structural information about the target or family of interest. In the absence of such structural information, a chemogenomic model that incorporates sequence and mutagenesis data to predict the properties of the binding site can be employed. A third option, usually pursued when no structural data are available, utilizes knowledge of the ligands of the target from which focused libraries can be developed via scaffold hopping. Consequently, the methods used for the design of target-focused libraries vary according to the quantity and quality of structural or ligand data that is available for each target family. This article describes examples of each of these design approaches and illustrates them with case studies, which highlight some of the issues and successes observed when screening target-focused libraries.
Highlights
Identifying novel and robust chemical starting points remains one of the biggest challenges in drug discovery today
The costly nature of such mass screening, the consequent need to use reductionist assays that are optimized primarily for scale and speed, and the increasing realization that drug property space is far from random has more recently led to the use of smaller, higher quality screening collections
A better strategy is to evaluate the scaffold by docking it into a representative subset of kinases, where each member is carefully chosen to represent a group of targets
Summary
Identifying novel and robust chemical starting points remains one of the biggest challenges in drug discovery today. In 1999, the BioFocus group pioneered the design and commercial production of novel target-focused libraries and, since its SoftFocus® range of libraries were first made available, they have contributed significantly to clients’ drug discovery efforts, leading to more than 100 patent filings [7] and nine published co-crystal structures, available from the Protein Data Bank (PDB) [8]: PDB codes 2R3A, 2R3G [9], 3F2A [10], 2C3I [11], 2PMN [12], 3IW8 [13], 3E7V, 3F2N and 3BQR. This paper illustrates the design methods used to target several distinct gene families, outlining a variety of different approaches available and showing the success of these approaches in several case studies It highlights how well-designed, targetfocused libraries give higher hit rates than diverse collections, often offering potent and selective molecular starting-points that can dramatically reduce the subsequent hit-to-lead timescale. Given the advantages of target-led approaches, where they are possible, over the erstwhile more popular diversityled paradigm, it is no surprise that the use of focused libraries is increasing
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