https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

A review of sterol markers for marine and terrigenous organic matter

: The unpolarized absorption and circular dichroism spectra of the fundamental vibrational transitions of the chiral molecule, 4-methyl-2-oxetanone, are calculated ab initio. Harmonic force fields are obtained using Density Functional Theory (DFT), MP2, and SCF methodologies and a 5S4P2D/3S2P (TZ2P) basis set. DFT calculations use the Local Spin Density Approximation (LSDA), BLYP, and Becke3LYP (B3LYP) density functionals. Mid-IR spectra predicted using LSDA, BLYP, and B3LYP force fields are of significantly different quality, the B3LYP force field yielding spectra in clearly superior, and overall excellent, agreement with experiment. The MP2 force field yields spectra in slightly worse agreement with experiment than the B3LYP force field. The SCF force field yields spectra in poor agreement with experiment.The basis set dependence of B3LYP force fields is also explored: the 6-31G* and TZ2P basis sets give very similar results while the 3-21G basis set yields spectra in substantially worse agreements with experiment. jg

Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields

NMR spectroscopy in the structural elucidation of oligosaccharides and glycosides.

Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities. Natural products have historically made a major contribution to pharmacotherapy, but also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization. This Review discusses recent technological developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — that are enabling a revitalization of natural product-based drug discovery.

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Natural products in drug discovery: advances and opportunities.

Sclerophytin C―F: isolation and structures of four new diterpenes from the soft coral Sclerophytum capitalis

COSY and NOESY frequently fail when key proton signals are poorly resolved because of the proximity of the correlating off-diagonal responses to the diagonal Proton-coupled heteronuclear multiple quantum relayed coherence spectroscopy (HMQC–TOCSY) and heteronuclear multiple quantum proton nuclear Overhauser effect (HMQC–NOESY) experiments to circumvent these problems are described NMR data for a model carbocyclic nucleoside analog are presented for which assignments of resonances and stereochemistry were impossible by ‘conventional’ 2D NMR methods Resonance and unequivocal stereochemical assignments were made, however, using the HMQC–TOCSY and HMQC–NOESY experiments, respectively

Disentangling coupling and NOE pathways involving poorly resolved proton signals: HMQC-TOCSY and HMQC-NOESY

Determining the net charge and protonation states populated by a small molecule in an environment of interest or the cost of altering those protonation states upon transfer to another environment is a prerequisite for predicting its physicochemical and pharmaceutical properties. The environment of interest can be aqueous, an organic solvent, a protein binding site, or a lipid bilayer. Predicting the protonation state of a small molecule is essential to predicting its interactions with biological macromolecules using computational models. Incorrectly modeling the dominant protonation state, shifts in dominant protonation state, or the population of significant mixtures of protonation states can lead to large modeling errors that degrade the accuracy of physical modeling. Low accuracy hinders the use of physical modeling approaches for molecular design. For small molecules, the acid dissociation constant (pKa) is the primary quantity needed to determine the ionic states populated by a molecule in an aqueous solution at a given pH. As a part of SAMPL6 community challenge, we organized a blind pKa prediction component to assess the accuracy with which contemporary pKa prediction methods can predict this quantity, with the ultimate aim of assessing the expected impact on modeling errors this would induce. While a multitude of approaches for predicting pKa values currently exist, predicting the pKas of drug-like molecules can be difficult due to challenging properties such as multiple titratable sites, heterocycles, and tautomerization. For this challenge, we focused on set of 24 small molecules selected to resemble selective kinase inhibitors—an important class of therapeutics replete with titratable moieties. Using a Sirius T3 instrument that performs automated acid–base titrations, we used UV absorbance-based pKa measurements to construct a high-quality experimental reference dataset of macroscopic pKas for the evaluation of computational pKa prediction methodologies that was utilized in the SAMPL6 pKa challenge. For several compounds in which the microscopic protonation states associated with macroscopic pKas were ambiguous, we performed follow-up NMR experiments to disambiguate the microstates involved in the transition. This dataset provides a useful standard benchmark dataset for the evaluation of pKa prediction methodologies on kinase inhibitor-like compounds.

p K a measurements for the SAMPL6 prediction challenge for a set of kinase inhibitor-like fragments

The development of new NMR probe technologies has been an active area of research effort for the past decade. Recently, cryogenically cooled NMR probes have been the subject of considerable interest in the light of the large gains in sensitivity and hence savings in spectrometer time that can be realized by utilizing this technology. With low gamma nuclides, such as 15N, time savings may be less of an issue than the ability to work with available samples rather than having to isolate additional material for analysis. Results of 5–10 Hz optimized CIGAR-HMBC 1H–15N experiments at natural abundance obtained using a 5 mm Varian 1H–15N Cryo-Q NMR probe are compared with those from a 3 mm gradient inverse triple resonance probe using a 2 mg sample of the oxazolidinone antibiotic eperezolid in a 3 mm NMR tube. Using the cryogenic NMR probe, a 1H–15N CIGAR-HMBC spectrum in which most previously reported long-range couplings are observed was recorded in ∼10 min; almost all of the expected long-range responses were observed within 26 min. Acquiring the same data set with identical parameters using a conventional 3 mm gradient inverse triple resonance probe gave data that were of substantially lower quality. Acquiring data comparable to the 26 min cryogenic probe data with the conventional 3 mm probe required ∼4 h to observe all of the responses and ∼18 h to obtain a spectrum with a signal-to-noise ratio comparable to the data set acquired with the cryogenic NMR probe. Copyright © 2001 John Wiley & Sons, Ltd.

Gary E. Martin

Papers

Sclerophytin C―F: isolation and structures of four new diterpenes from the soft coral Sclerophytum capitalis

Disentangling coupling and NOE pathways involving poorly resolved proton signals: HMQC-TOCSY and HMQC-NOESY

p K a measurements for the SAMPL6 prediction challenge for a set of kinase inhibitor-like fragments

Applications of cryogenic NMR probe technology to long-range 1H-15N 2D NMR studies at natural abundance

Decoupling modulations due to one-bond heteronuclear spin couplings in long-range heteronuclear chemical-shift correlation spectra