The CryoEM Method MicroED as a Powerful Tool for Small Molecule Structure Determination

Jones, Callum; Martynowycz, Michael W.; Hattne, Johan; Fulton, Tyler J.; Stoltz, Brian M.; Rodríguez, José Antonio; Nelson, Hosea M.; Gonen, Tamir

doi:10.26434/chemrxiv.7215332

Cited by 52 publications

(66 citation statements)

References 12 publications

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“…A completely different approach to determine the structure of small organic molecules is presented by the new method: cryo-electron microscopy/microcrystal electron diffraction CryoEM/MicroED [ 63 ]. It enables collecting the high-quality MicroED data from nanocrystals, which results in atomic resolution (<1 Å) crystal structures.…”

Section: Methods Applied For Analysis Of Hydratesmentioning

confidence: 99%

Pharmaceutical Hydrates Analysis—Overview of Methods and Recent Advances

et al. 2020

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This review discusses a set of instrumental and computational methods that are used to characterize hydrated forms of APIs (active pharmaceutical ingredients). The focus has been put on highlighting advantages as well as on presenting some limitations of the selected analytical approaches. This has been performed in order to facilitate the choice of an appropriate method depending on the type of the structural feature that is to be analyzed, that is, degree of hydration, crystal structure and dynamics, and (de)hydration kinetics. The presented techniques include X-ray diffraction (single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD)), spectroscopic (solid state nuclear magnetic resonance spectroscopy (ssNMR), Fourier-transformed infrared spectroscopy (FT-IR), Raman spectroscopy), thermal (differential scanning calorimetry (DSC), thermogravimetric analysis (TGA)), gravimetric (dynamic vapour sorption (DVS)), and computational (molecular mechanics (MM), Quantum Mechanics (QM), molecular dynamics (MD)) methods. Further, the successful applications of the presented methods in the studies of hydrated APIs as well as studies on the excipients’ influence on these processes have been described in many examples.

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Section: Methods Applied For Analysis Of Hydratesmentioning

confidence: 99%

Pharmaceutical Hydrates Analysis—Overview of Methods and Recent Advances

et al. 2020

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“…The bottleneck of transcriptional silence continues to drive innovation and a plethora of different approaches exist to activate silent pathways [199][200][201] . Advances in analytical techniques (mass spectrometry, NMR imaging and data analysis software) [202][203][204][205] allow us to better detect and characterize compounds produced in minute quantities, a major bottleneck in the field, lifting the veil on 'silent' NPs to further increase the number of unusual molecule leads, in addition to identifying critical pathway intermediates that may aid in deciphering cryptic pathways. The ability to isolate and characterize unstable, cryptic NPs such as colibactin 206 is also improving with advances in our understanding of NP biosynthesis and its regulation, in addition to the development of reactivity-based screening protocols that target specific functional groups 207,208 .…”

Section: Unlocking Nature's Diversitymentioning

confidence: 99%

The hidden enzymology of bacterial natural product biosynthesis

Scott

Piel

2019

Nat Rev Chem

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Bacterial natural products display astounding structural diversity, which, in turn, endows them with a remarkable range of biological activities that are of significant value to modern society. Such structural features are generated by biosynthetic enzymes that construct core scaffolds or perform peripheral modifications, and can thus define natural product families, introduce pharmacophores and permit metabolic diversification. Modern genomics approaches have greatly enhanced our ability to access and characterize natural product pathways via sequence-similaritybased bioinformatics discovery strategies. However, many biosynthetic enzymes catalyse exceptional, unprecedented transformations that continue to defy functional prediction and remain hidden from us in bacterial (meta)genomic sequence data. In this Review, we highlight exciting examples of unusual enzymology that have been uncovered recently in the context of natural product biosynthesis. These suggest that much of the natural product diversity, including entire substance classes, awaits discovery. New approaches to lift the veil on the cryptic chemistries of the natural product universe are also discussed. Bacterial natural products (NPs) are specialized metabolites that encompass an extraordinary breadth of different biological activities, many of which are of considerable value to society. NPs or NP-inspired compounds represent ~65% of all small-molecule approved drugs 1 used in medicine to treat infectious diseases, cancers or as immunosuppressants 2 , and they are also applied extensively in agriculture 3. While NPs have been an extremely productive source of new leads for the chemicals that are integral to modern life, rapid increases in resistance to antibiotics, cancer chemotherapies and pesticides pose significant threats to medicine and agriculture 4,5 .

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“…Compounds 2-8 were present in quite small amounts and had weak optical rotations and CD curves; therefore, their absolute configurations could not be deduced, but perhaps may be resolved in the future by new and innovative approaches such as MicroED (Jones et al, 2018).…”

Section: Structural Elucidation Of Compounds 1-8mentioning

confidence: 99%

Monomeric and Dimeric Bromophenols from the Red Alga Ceramium Sp. with Antioxidant and Anti-Inflammatory Activities

Zhang¹,

Glukhov²,

Yu³

et al. 2020

Preprint

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LC-MS2-based molecular networking using the Global Natural Products Social (GNPS) tool revealed a rich assortment of brominated compounds present in the antioxidant fraction of a red algal extract (Ceramium sp.) Further chemical investigation led to discovery of one monomeric bromophenol (lanosol isopropyl ether, 1) and seven dimeric ones (bromourceolatols A-G, 2-8), all of which are previously undescribed. Their structures were elucidated by extensive analysis of their spectroscopic data. Compounds 2-8 were determined to be racemic trans-type isomers by NOESY, specific optical rotation, and ECD. Compounds 1 and 3 displayed antioxidant activity with their EC50 of 44.4 and 47.0 μM, respectively, for scavenging DPPH free radicals while compounds 2 and 4 had approximate EC50 values of ~ 64 μM. Furthermore, compounds 2, 3, and 7 exhibited relatively potent anti-inflammatory activity at 32 μM by quenching 97%, 47%, and 73% of nitric oxide induced by bacterial lipopolysaccharide in macrophage RAW264.7 cells, respectively.

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The CryoEM Method MicroED as a Powerful Tool for Small Molecule Structure Determination

Cited by 52 publications

References 12 publications

Pharmaceutical Hydrates Analysis—Overview of Methods and Recent Advances

Pharmaceutical Hydrates Analysis—Overview of Methods and Recent Advances

The hidden enzymology of bacterial natural product biosynthesis

Monomeric and Dimeric Bromophenols from the Red Alga Ceramium Sp. with Antioxidant and Anti-Inflammatory Activities

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