The rise of fragment-based drug discovery

Abstract

The search for new drugs is plagued by high attrition rates at all stages in research and development. Chemists have an opportunity to tackle this problem because attrition can be traced back, in part, to the quality of the chemical leads. Fragment-based drug discovery (FBDD) is a new approach, increasingly used in the pharmaceutical industry, for reducing attrition and providing leads for previously intractable biological targets. FBDD identifies low-molecular-weight ligands (∼150 Da) that bind to biologically important macromolecules. The three-dimensional experimental binding mode of these fragments is determined using X-ray crystallography or NMR spectroscopy, and is used to facilitate their optimization into potent molecules with drug-like properties. Compared with high-throughput-screening, the fragment approach requires fewer compounds to be screened, and, despite the lower initial potency of the screening hits, offers more efficient and fruitful optimization campaigns. Here, we review the rise of FBDD, including its application to discovering clinical candidates against targets for which other chemistry approaches have struggled.

A Monod-Wyman-Changeux Mechanism Can Explain G Protein-coupled Receptor (GPCR) Allosteric Modulation

“…Such low (micromolar to millimolar) affinity is commonly seen in fragmentbased drug discovery, and thus an additional implication of our results is that it may be possible to identify novel allosteric modulators among fragment libraries using traditional cell-based assays rather than the current paradigm that relies on biophysical and structural approaches (41). Although speculative, it may also be that the "fragment-like" nature of BQCA imposes an inherent limit to the number of receptor conformations that such a simple molecule can sample, thus providing an additional mechanism to account for its two-state behavior.…”

Detection of secondary binding sites in proteins using fragment screening

“…The emergence of fragment-based drug discovery as an approach to identify novel small-molecule drug candidates has been well documented in recent years (16). In particular, screening of fragment libraries using X-ray crystallography has been shown to be a rather effective approach to sample chemical space, revealing previously unobserved pockets and ligand binding modes.…”

Allosteric Tuning of Caspase‐7: A Fragment‐Based Drug Discovery Approach

“…Typical high‐throughput screening methods attempt to identify potent chemical leads (<10 μ m ) by screening upwards of millions of rule‐of‐five compliant small molecules (<500 Da) 6. By screening small libraries of hundreds to thousands of fragment molecules (<300 Da), it is possible to sample far greater chemical diversity 7. While fragments identified by FBDD have low affinity (μ m –m m ), they possess higher ligand efficiency and represent strong foundations for drug discovery efforts.…”