Twenty years on: the impact of fragments on drug discovery

Erlanson, Daniel A.; Fesik, Stephen W.; Hubbard, Roderick E.; Jahnke, Wolfgang; Jhoti, Harren

doi:10.1038/nrd.2016.109

Cited by 798 publications

(871 citation statements)

References 107 publications

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“…Possible strategies include: 1) Copying Nature and using repetitive coupling chemistries to easily build different systems out of a family of building blocks (peptidomimetics); 43 2) Embracing robotic/automation for targeted syntheses and/or accelerated serendipity approaches 114 to host design; 3) Using fragment-based approaches and structurebased design. 115 Within the physical community, one ongoing debate involves the solvation of proteins and how this influences their properties. There is good evidence that the large-amplitude motions of proteins are mediated by the translational diffusion of water.…”

Section: Recognition Mimicry and Interactions With Biomoleculesmentioning

confidence: 99%

Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry

et al. 2017

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Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry. AbstractOn planet Earth, water is everywhere: the majority of the surface is covered with it; it is a key component of all life; its vapor and droplets fill the lower atmosphere; even rocks contain it and undergo geomorphological changes because of it. A community of physical scientists largely drives studies of the chemistry of water and aqueous solutions, with expertise in biochemistry, spectroscopy, and computer modeling. More recently however, supramolecular chemistry -with its expertise in macrocyclic synthesis and measuring supramolecular interactions -have renewed their interest in water-mediated non-covalent interactions. These two groups offer complementary expertise that, if harnessed, offers to accelerate our understanding of aqueous supramolecular chemistry and water writ large. This review summarizes the state-of-the-art of the two fields, and highlights where there is latent chemical space for collaborative exploration by the two groups. 4Water is ubiquitous and essential to life on planet Earth. A full understanding of aqueous solutions is therefore of significance to a wide range of fields within the atmospheric, environmental, biological and geological sciences. Within the chemical sciences, a deeper appreciation of how non-covalent interactions and chemical transformations are influenced by water would benefit a variety of fields. However, as we highlight here, there are many open questions regarding the chemical and physical properties of aqueous solutions.The aqueous realm is frequently bifurcated into the Hofmeister and hydrophobic effects, phenomena that respectively deal with the properties of solutions of salts and relatively nonpolar molecules. However, it is becoming increasingly evident that these areas do in fact frequently overlap; two prime examples being the accumulation of large polarizable anions at the air-water interface, 1-5 and the favorable interactions of polarizable anions with non-polar surfaces. [6][7][8][9][10][11][12][13][14][15] Thus the hydrophobic and Hofmeister effects are but part of a greater continuum of aqueous supramolecular chemistry, with many important and outstanding questions regarding the influence of the different kinds of non-covalent interactions involved.Studies of water and aqueous solutions have mostly been driven by the physical sciences community, a broad range of scientists whose expertise in spectroscopy, computer modeling, and biochemistry (to name just three areas) has generally not involved macrocycles or host molecules in general. However, for some time now, supramolecular chemists -with their expertise in macrocyclic synthesis and measuring weak non-covalent interactions -have been travelling a parallel course of exploration. This Review, inspired by discussions between sixteen members of each community at a recent workshop, 16 is an attempt to summarize what we know about aqueous solutions, what we do not know about them, and where the two communit...

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Section: Recognition Mimicry and Interactions With Biomoleculesmentioning

confidence: 99%

Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry

et al. 2017

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“…13 That journey represents a milestone in drug discovery science, in that it entailed the first successful application of the so-called SAR by NMR (structureactivity relation by nuclear magnetic resonance) technology to tackle a very challenging protein-protein interaction target, an accomplishment recently recognized with the 2017 Prix Galien. 14 In addition to the countless scientific, technical, medical and other professionals who contributed to that drug, Abbvie management also deserves praise for allowing protracted investment in the Bcl-2 inhibitor program over a time frame that few companies would have courage to continue.…”

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Bcl-2 on the brink of breakthroughs in cancer treatment

Reed

2017

Cell Death Differ

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“…It is possible that current screening libraries do not contain an appropriate complementary chemical space. Over the last twenty years, fragment‐based drug discovery (FBDD) has emerged as a powerful, complementary method for the generation of new chemical hits 5. 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.…”

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

2017

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The caspase family of cysteine proteases are highly sought‐after drug targets owing to their essential roles in apoptosis, proliferation, and inflammation pathways. High‐throughput screening efforts to discover inhibitors have gained little traction. Fragment‐based screening has emerged as a powerful approach for the discovery of innovative drug leads. This method has become a central facet of drug discovery campaigns in the pharmaceutical industry and academia. A fragment‐based drug discovery campaign against human caspase‐7 resulted in the discovery of a novel series of allosteric inhibitors. An X‐ray crystal structure of caspase‐7 bound to a fragment hit and a thorough kinetic characterization of a zymogenic form of the enzyme were used to investigate the allosteric mechanism of inhibition. This work further advances our understanding of the mechanisms of allosteric control of this class of pharmaceutically relevant enzymes, and provides a new path forward for drug discovery efforts.

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Twenty years on: the impact of fragments on drug discovery

Cited by 798 publications

References 107 publications

Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry

Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry

Bcl-2 on the brink of breakthroughs in cancer treatment

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

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