Fragment Libraries

The major limitation in fragment-based screening is the weak binding affinity of fragment hits, which not only necessitates very sensitive biophysical detection methods but also makes progressing hits to potency difficult and expensive. In particular, it requires a large compound series with typically ambiguous structure–activity relationships, because no method to date can reliably rationalize which are the dominant interactions of the original fragment. Screening covalent fragments addresses these limitations. Covalent binders are easy to detect by mass spectrometry, because the dominant interaction is unambiguous (namely, the covalent bond), which simplifies the design of follow-up series, and because the primary hits are already potent

A major challenge in modern drug discovery and chemical biology is the ability to identify inhibitors of protein–protein interactions (PPIs). In recent years, fragment-based approaches targeting PPIs have emerged as a new methodology that is aimed to address this challenge. Comparative analysis of “normal” fragments with those targeting PPIs has revealed that the latter tend to be larger, be more lipophilic, and contain more polar (acid/base) functionality. These physicochemical properties correlate well with optimized PPI inhibitors and are exploited in the rational design of PPI-specific fragment libraries.

Recently, halogen bonds have gained increased recognition as a useful molecular interaction in the life sciences and drug discovery. However, despite the potential of halogen moieties to positively affect ligand binding, standard libraries for fragment-based screening display very low number of compounds containing heavy halides. Halogen-enriched fragment libraries (HEFLibs) consist of chemical probes that allow to identify halogen bonds as one of the main features of the protein-ligand binding mode. Besides that, these fragment libraries provide smart starting points for hit-to-lead evolution.

The principles of metal chelation provide significant opportunities for drug design that go beyond traditional notions of chelation as metal sequestration and elimination. Exploring these other possibilities could lead to pharmacological interventions that alter the concentration, distribution, or reactivity of metals in targeted ways for therapeutic benefit. A good example is fragment-based lead design (FBLD) that has been used to identify new metal-binding groups for metalloenzyme inhibitors. This and other approaches exploit the presence of the metal ion in these enzymes for the development of synthetic small molecules with therapeutic potential.

Natural products have contributed to the development of many drugs for diverse indications and they continue to be an important source of leads for new medicines, despite reduced interest from large pharmaceutical companies. The development of new technologies including fragment-based drug discovery (FBDD) has revolutionized the screening of natural products as potential therapeutic agents.

In the past decade, fragment based drug design (FBDD) has risen as a new and effective approach to identify lead compounds and continues to show great promise in drug discovery. It requires the use of sensitive techniques such as X-ray crystallography to identify hits among low molecular weight fragment compounds that have a weak binding affinity to a drug target. The hit fragments could be then structurally optimized to lead compounds with high affinity and specificity.