Realisation of small molecule libraries based on frameworks distantly related to natural products

Aimon, A.; Karageorgis, George; Masters, Jacob; Dow, Mark; Craven, Philip; Rasmussen, Martin Ohsten; Willaume, Anthony; Morgentin, Rémy; Ruiz-Llamas, Nicolas; Lemoine, Hugues; Kalliokoski, Tuomo; Eatherton, Andrew J.; Foley, Daniel J.; Marsden, S. P.; Nelson, Adam

doi:10.1039/c8ob00688a

Cited by 17 publications

(13 citation statements)

References 24 publications

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Section: Resultsmentioning

confidence: 99%

“…Two libraries were employed. The first, the Leeds three-dimensional collection [25,26], comprises 125 fragments with fewer planar chemical groups and more natural-product-like scaffolds. Fragments from this library have high sp 3 ) can also be seen in addition to the three hotspots, when the maps are contoured at 14 and the hydrophobic patches (yellow) at all the hotspot regions become more prominent at this contour.…”

Section: (D) Fragment Screening Using Xchem and Pandda With A Diverse Librarymentioning

confidence: 99%

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Structure-guided fragment-based drug discovery at the synchrotron: screening binding sites and correlations with hotspot mapping

Thomas

Collins

James

et al. 2019

Phil. Trans. R. Soc. A.

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Structure-guided drug discovery emerged in the 1970s and 1980s, stimulated by the three-dimensional structures of protein targets that became available, mainly through X-ray crystal structure analysis, assisted by the development of synchrotron radiation sources. Structures of known drugs or inhibitors were used to guide the development of leads. The growth of high-throughput screening during the late 1980s and the early 1990s in the pharmaceutical industry of chemical libraries of hundreds of thousands of compounds of molecular weight of approximately 500 Da was impressive but still explored only a tiny fraction of the chemical space of the predicted 10 40 drug-like compounds. The use of fragments with molecular weights less than 300 Da in drug discovery not only decreased the chemical space needing exploration but also increased promiscuity in binding targets. Here we discuss advances in X-ray fragment screening and the challenge of identifying sites where fragments not only bind but can be chemically elaborated while retaining their positions and binding modes. We first describe the analysis of fragment binding using conventional X-ray difference Fourier techniques, with Mycobacterium abscessus SAICAR synthetase (PurC) as an example. We observe that all fragments occupy positions predicted by computational hotspot mapping. We compare this with fragment screening at Diamond Synchrotron Light Source XChem facility using PanDDA software, which identifies many more fragment hits, only some of which bind to the predicted hotspots. Many low occupancy sites identified may not support elaboration to give adequate ligand affinity, although they will likely be useful in drug discovery as ‘warm spots’ for guiding elaboration of fragments bound at hotspots. We discuss implications of these observations for fragment screening at the synchrotron sources. This article is part of the theme issue ‘Fifty years of synchrotron science: achievements and opportunities’.

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Section: Resultsmentioning

confidence: 99%

Section: (D) Fragment Screening Using Xchem and Pandda With A Diverse Librarymentioning

confidence: 99%

Structure-guided fragment-based drug discovery at the synchrotron: screening binding sites and correlations with hotspot mapping

Thomas

Collins

James

et al. 2019

Phil. Trans. R. Soc. A.

View full text Add to dashboard Cite

show abstract

“…This means that chemistry feasibility should not be an issue when evolving the initial hits. With p38α, we additionally tested fragments from the Leeds3D , and Maybridge core 1000 Ro3 libraries.…”

Section: Discussionmentioning

confidence: 99%

Mining the PDB for Tractable Cases Where X-ray Crystallography Combined with Fragment Screens Can Be Used to Systematically Design Protein–Protein Inhibitors: Two Test Cases Illustrated by IL1β-IL1R and p38α–TAB1 Complexes

Nichols

Keshu

et al. 2020

J. Med. Chem.

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Nowadays, it is possible to combine X-ray crystallography and fragment screening in a medium throughput fashion to chemically probe the surfaces used by proteins to interact and use the outcome of the screens to systematically design protein− protein inhibitors. To prove it, we first performed a bioinformatics analysis of the Protein Data Bank protein complexes, which revealed over 400 cases where the crystal lattice of the target in the free form is such that large portions of the interacting surfaces are free from lattice contacts and therefore accessible to fragments during soaks. Among the tractable complexes identified, we then performed single fragment crystal screens on two particular interesting cases: the Il1β-ILR and p38α-TAB1 complexes. The result of the screens showed that fragments tend to bind in clusters, highlighting the small-molecule hotspots on the surface of the target protein. In most of the cases, the hotspots overlapped with the binding sites of the interacting proteins.

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“…Examples of such properties include high Fsp 3 character, 17 a three-dimensional (3D) shape, 18 the ability to form covalent bonds with the target, 19 protein–protein interface binding character, 20 or natural product resemblance. 17 …”

Section: Introductionmentioning

confidence: 99%

Fragment Libraries Designed to Be Functionally Diverse Recover Protein Binding Information More Efficiently Than Standard Structurally Diverse Libraries

et al. 2022

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Current fragment-based drug design relies on the efficient exploration of chemical space by using structurally diverse libraries of small fragments. However, structurally dissimilar compounds can exploit the same interactions and thus be functionally similar. Using three-dimensional structures of many fragments bound to multiple targets, we examined if a better strategy for selecting fragments for screening libraries exists. We show that structurally diverse fragments can be described as functionally redundant, often making the same interactions. Ranking fragments by the number of novel interactions they made, we show that functionally diverse selections of fragments substantially increase the amount of information recovered for unseen targets compared to the amounts recovered by other methods of selection. Using these results, we design small functionally efficient libraries that can give significantly more information about new protein targets than similarly sized structurally diverse libraries. By covering more functional space, we can generate more diverse sets of drug leads.

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Realisation of small molecule libraries based on frameworks distantly related to natural products

Cited by 17 publications

References 24 publications

Structure-guided fragment-based drug discovery at the synchrotron: screening binding sites and correlations with hotspot mapping

Structure-guided fragment-based drug discovery at the synchrotron: screening binding sites and correlations with hotspot mapping

Mining the PDB for Tractable Cases Where X-ray Crystallography Combined with Fragment Screens Can Be Used to Systematically Design Protein–Protein Inhibitors: Two Test Cases Illustrated by IL1β-IL1R and p38α–TAB1 Complexes

Fragment Libraries Designed to Be Functionally Diverse Recover Protein Binding Information More Efficiently Than Standard Structurally Diverse Libraries

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