Abstract
Fragment-based drug discovery (FBDD) concerns the screening of low-molecular weight compounds against macromolecular targets of clinical relevance. These compounds act as starting points for the development of drugs. FBDD has evolved and grown in popularity over the past 15 years. In this paper, the rationale and technology behind the use of X-ray crystallography in fragment based screening (FBS) will be described, including fragment library design and use of synchrotron radiation and robotics for high-throughput X-ray data collection. Some recent uses of crystallography in FBS will be described in detail, including interrogation of the drug targets β-secretase, phenylethanolamine N-methyltransferase, phosphodiesterase 4A and Hsp90. These examples provide illustrations of projects where crystallography is straightforward or difficult, and where other screening methods can help overcome the limitations of crystallography necessitated by diffraction quality.
Highlights
Contemporary drug discovery efforts are aimed at modulating the activities of specific targets
The origins of fragment-based drug discovery (FBDD) are debatable, but it has been documented [2] that X-ray crystallography was first used to map the interactions of small-molecule organic solvents on protein surfaces [3,4]
The cAMP-degrading phosphodiesterase 4 (PDE4) family of enzymes is a potential target for therapeutics for the treatment of chronic obstructive pulmonary disease (COPD), asthma, depression and neurodegenerative diseases
Summary
Contemporary drug discovery efforts are aimed at modulating the activities of specific targets (almost always a protein that is essential to a pathogen, or a human protein that is misregulated, misfolded or mutated). Starting-points for chemical leads include natural products, high throughput screening (HTS) of large chemical libraries, and most recently fragment-based drug discovery (FBDD). The latter is a method that has evolved over the past ~20 years for generating high affinity ligands to serve as starting points for the development of drug candidates [1]. HTS hits, and fragment-screening techniques need sufficient sensitivity to detect hits with Kd values in the mM to high μM range This low affinity is partly a consequence of overcoming a rigid body entropic barrier, estimated to be 15–20 kJ/mol (or 3 orders of magnitude in Kd) at 298 K [14].
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