Site‐Directed Fragment Discovery for Allostery

Rettenmaier, T.J.; Hudson, Sean A.; Wells, James A.

doi:10.1002/9783527683604.ch11

Cited by 2 publications

(1 citation statement)

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“…Tethering/Covalent Fragments Since the approval and commercial success of ibrutinib, covalent drugs have become more acceptable, and this applies to fragments as well. An early application of covalent lead discovery is Tethering, in which a disulfide bond between a fragment and a cysteine in a protein stabilizes the interactions, sometimes allowing crystal structures to be determined for fragments that bind too weakly to detect in the absence of the disulfide (Erlanson et al, 2000;Kathman and Statsyuk, 2016;Rettenmaier et al, 2016). Even in the absence of a crystal structure, the known site of binding can enable modeling and medicinal chemistry, as demonstrated by the discovery of highly selective, noncovalent inhibitors of the kinase PDK1 (Erlanson et al, 2011).…”

Section: Chemical Approachesmentioning

confidence: 99%

Fragment-Based Drug Discovery: Advancing Fragments in the Absence of Crystal Structures

Erlanson

Davis

Jahnke

2019

Cell Chemical Biology

106

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Fragment-based drug discovery typically requires an interplay between screening methods, structural methods, and medicinal chemistry. X-ray crystallography is generally the method of choice to obtain three-dimensional structures of the bound ligand/protein complex, but this can sometimes be difficult, particularly for early, low-affinity fragment hits. In this Perspective, we discuss strategies to advance and evolve fragments in the absence of crystal structures of protein-fragment complexes, although the structure of the unliganded protein may be available. The strategies can involve other structural techniques, such as NMR spectroscopy, molecular modeling, or a variety of chemical approaches. Often, these strategies are aimed at guiding evolution of initial fragment hits to a stage where crystal structures can be obtained for further structure-based optimization. Essentially, all models are wrong, but some are useful.

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Section: Chemical Approachesmentioning

confidence: 99%

Fragment-Based Drug Discovery: Advancing Fragments in the Absence of Crystal Structures

Erlanson

Davis

Jahnke

2019

Cell Chemical Biology

106

View full text Add to dashboard Cite

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Fragment-Based Approaches for Allosteric Metabotropic Glutamate Receptor (mGluR) Modulators

Orgován

Ferenczy

Keserü

2019

CTMC

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Metabotropic glutamate receptors (mGluR) are members of the class C G-Protein Coupled Receptors (GPCR-s) and have eight subtypes. These receptors are responsible for a variety of functions in the central and peripheral nervous systems and their modulation has therapeutic utility in neurological and psychiatric disorders. It was previously established that selective orthosteric modulation of these receptors is challenging, and this stimulated the search for allosteric modulators. Fragment-Based Drug Discovery (FBDD) is a viable approach to find ligands binding at allosteric sites owing to their limited size and interactions. However, it was also observed that the structure-activity relationship of allosteric modulators is often sharp and inconsistent. This can be attributed to the characteristics of the allosteric binding site of mGluRs that is a water channel where ligand binding is accompanied with induced fit and interference with the water network, both playing a role in receptor activation. In this review, we summarize fragment-based drug discovery programs on mGluR allosteric modulators and their contribution identifying of new mGluR ligands with better activity and selectivity.

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Site‐Directed Fragment Discovery for Allostery

Cited by 2 publications

References 40 publications

Fragment-Based Drug Discovery: Advancing Fragments in the Absence of Crystal Structures

Fragment-Based Drug Discovery: Advancing Fragments in the Absence of Crystal Structures

Fragment-Based Approaches for Allosteric Metabotropic Glutamate Receptor (mGluR) Modulators

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