In particular, it highlights how well-designed, target-focused 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.Some guidelines related to the SAR issue have been proposed .When deciding the minimum size of the library several factors need to be considered including the tractability of the target, maximizing the efficiency of the chemistry and the importance of observing initial structure-activity relationships (SAR) in the hit clusters.Given the advantages of target-led approaches, where they are possible, over the erstwhile more popular diversity-led paradigm, it is no surprise that the use of focused libraries is increasing.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.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 and nine published co-crystal structures, available from the Protein Data Bank (PDB): PDB codes 2R3A, 2R3G, 3F2A, 2C3I, 2PMN, 3IW8, 3E7V, 3F2N and 3BQR.
Focused libraries may be selected from larger, more diverse collections using computational techniques such as in silico docking to the target or ligand similarity calculations using molecular fingerprints.Target-focused libraries are often based around a single core or scaffold with one or more (typically 2 or 3) attachment points to which are appended specific substituents, or side chains, to arrive at the desired molecules.Target-focused libraries are designed based upon some understanding of the target or target family of interest.Generally, a subset of these is chosen for synthesis, often around 100-500 compounds, selected to fully explore the design hypothesis efficiently and to adhere to drug-like properties.This retrospective approach to the selection of compounds has been reviewed elsewhere; the focus of this article is the rational, prospective design of target-focused libraries.
Alternatively, approaches based on the properties of known ligands can be deployed; these are applicable to all targets and target families provided that high quality ligand data are available such approaches offer a useful way of scaffold hopping from one ligand class to another.A scaffold diversified at two or three attachment points of diversity would, if all possible combinations were considered, generate a library of many thousands of compounds.The design can be based on target structural data (commonly used in the kinase, protease or nuclear receptor fields where crystallographic data are abundant), or, where target structural data are more scarce but sequence data and mutagenesis data are abundant, on broader chemogenomic principles (for example, with GPCR and ion channel targets).
Several complementary strategies are employed in screening: the use of diverse small molecule libraries, target-focused libraries, natural products, and fragment collections.The premise of screening such a library is that fewer compounds need to be screened in order to obtain hit compounds.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.Over the last decade, it has been common practice during the early stage of a project to screen vast numbers of compounds in high-throughput assays in order to identify those chemicals which have the potential to modulate the target of interest.A target-focused library is a collection of compounds which has been either designed or assembled with a protein target or protein family in mind.Identifying novel and robust chemical starting points remains one of the biggest challenges in drug discovery today.In particular, experience has shown that eliminating compounds with undesirable molecular features, be they overt (e.Most organizations now tend to prefer highly curated collections which have been selected to be drug-like or lead-like and to have high ligand efficiency.Many strategies exist that seek to build such optimal initial screening collections.The type of compounds selected for these collections is of the utmost importance.All of these approaches have their own particular advantages and disadvantages.
Furthermore, it is generally the case that higher hit rates are observed when compared with the screening of diverse sets, and the hit clusters obtained from a successful focused library screening campaign usually exhibit discernable structure-activity relationships that facilitate follow up of these hits.