Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

New insight on the structural features of the cytotoxic auristatins MMAE and MMAF revealed by combined NMR spectroscopy and quantum chemical modelling.

ABSTRACT: Antibody-drug conjugates (ADCs) are emerging as a promising class of selective drug delivery systems in the battle against cancer and other diseases. The auristatins monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) appear as the cytotoxic drug in almost half of the state-of-the-art ADCs on the market or in late stage clinical trials. Here, we present the first complete NMR spectroscopic characterisation of these challenging molecules, and investigate their structural properties by a combined NMR and quantum chemical modelling approach. We find that in solution, half of the drug molecules are locked in an inactive conformation, severely decreasing their efficiency, and potentially increasing the risk of side-effects. Furthermore, we identify sites susceptible to future modification, in order to potentially improve the performance of these drugs.

SUBMITTER: Johansson MP

PROVIDER: S-EPMC5698355 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

New insight on the structural features of the cytotoxic auristatins MMAE and MMAF revealed by combined NMR spectroscopy and quantum chemical modelling.

Johansson Mikael P MP Maaheimo Hannu H Ekholm Filip S FS

Scientific reports 20171121 1

Antibody-drug conjugates (ADCs) are emerging as a promising class of selective drug delivery systems in the battle against cancer and other diseases. The auristatins monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) appear as the cytotoxic drug in almost half of the state-of-the-art ADCs on the market or in late stage clinical trials. Here, we present the first complete NMR spectroscopic characterisation of these challenging molecules, and investigate their structural properties ...[more]

PMID: 29162861

Similar Datasets

Ensemble quantum computing by NMR spectroscopy.

Project description:A quantum computer (QC) can operate in parallel on all its possible inputs at once, but the amount of information that can be extracted from the result is limited by the phenomenon of wave function collapse. We present a new computational model, which differs from a QC only in that the result of a measurement is the expectation value of the observable, rather than a random eigenvalue thereof. Such an expectation value QC can solve nondeterministic polynomial-time complete problems in polynomial time. This observation is significant precisely because the computational model can be realized, to a certain extent, by NMR spectroscopy on macroscopic ensembles of quantum spins, namely molecules in a test tube. This is made possible by identifying a manifold of statistical spin states, called pseudo-pure states, the mathematical description of which is isomorphic to that of an isolated spin system. The result is a novel NMR computer that can be programmed much like a QC, but in other respects more closely resembles a DNA computer. Most notably, when applied to intractable combinatorial problems, an NMR computer can use an amount of sample, rather than time, which grows exponentially with the size of the problem. Although NMR computers will be limited by current technology to exhaustive searches over only 15 to 20 bits, searches over as much as 50 bits are in principle possible, and more advanced algorithms could greatly extend the range of applicability of such machines.

| S-EPMC19968 | biostudies-other

Combined NMR Spectroscopy and Quantum-Chemical Calculations in Fluorescent 1,2,3-Triazole-4-carboxylic Acids Fine Structures Analysis.

Project description:The peculiarities of the optical properties of 2-aryl-1,2,3-triazole acids and their sodium salts were investigated in different solvents (1,4-dioxane, dimethyl sulfoxide DMSO, methanol MeOH) and in mixtures with water. The results were discussed in terms of the molecular structure formed by inter- and intramolecular noncovalent interactions (NCIs) and their ability to ionize in anions. Theoretical calculations using the Time-Dependent Density Functional Theory (TDDFT) were carried out in different solvents to support the results. In polar and nonpolar solvents (DMSO, 1,4-dioxane), fluorescence was provided by strong neutral associates. Protic MeOH can weaken the acid molecules' association, forming other fluorescent species. The fluorescent species in water exhibited similar optical characteristics to those of triazole salts; therefore, their anionic character can be assumed. Experimental 1H and 13C-NMR spectra were compared to their corresponding calculated spectra using the Gauge-Independent Atomic Orbital (GIAO) method and several relationships were established. All these findings showed that the obtained photophysical properties of the 2-aryl-1,2,3-triazole acids noticeably depend on the environment and, therefore, are good candidates as sensors for the identification of analytes with labile protons.

| S-EPMC10219572 | biostudies-literature

Tautomerism of Warfarin: Combined Chemoinformatics, Quantum Chemical, and NMR Investigation.

Project description:Warfarin, an important anticoagulant drug, can exist in solution in 40 distinct tautomeric forms through both prototropic tautomerism and ring-chain tautomerism. We have investigated all warfarin tautomers with computational and NMR approaches. Relative energies calculated at the B3LYP/6-311G++(d,p) level of theory indicate that the 4-hydroxycoumarin cyclic hemiketal tautomer is the most stable tautomer in aqueous solution, followed by the 4-hydroxycoumarin open-chain tautomer. This is in agreement with our NMR experiments where the spectral assignments indicate that warfarin exists mainly as a mixture of cyclic hemiketal diastereomers, with an open-chain tautomer as a minor component. We present a diagram of the interconversion of warfarin created taking into account the calculated equilibrium constants (pK(T)) for all tautomeric reactions. These findings help with gaining further understanding of proton transfer and ring closure tautomerization processes. We also discuss the results in the context of chemoinformatics rules for handling tautomerism.

| S-EPMC7724503 | biostudies-literature

Bolalipid membrane structure revealed by solid-state 2H NMR spectroscopy.

Project description:Membranes made from three specifically deuterium-labeled ether-linked bolalipids, [1',1',20',20'-2H4]C20BAS-PC, [2',2',19',19'-2H4]C20BAS-PC, or [10',11'-2H2]C20BAS-PC, were analyzed by 2H NMR spectroscopy. Unlike more common monopolar, ester-linked phospholipids, C20BAS-PC exhibits a high degree of orientational order throughout the membrane and the sn-1 chain of the lipid initially penetrates the bilayer at an orientation different from that of the bilayer normal, resulting in inequivalent deuterium atoms at the C1 position. The approximate hydrophobic layer thickness and area per lipid are 18.4 A and 60.4 A2, respectively, at 25 degrees C, and their respective thermal expansion coefficients are within 20% of the monopolar phospholipid, DLPC.

| S-EPMC5176267 | biostudies-literature

NMR spectroscopy of human eye tissues: a new insight into ocular biochemistry.

Project description:BACKGROUND: The human eye is a complex organ whose anatomy and functions has been described very well to date. Unfortunately, the knowledge of the biochemistry and metabolic properties of eye tissues varies. Our objective was to reveal the biochemical differences between main tissue components of human eyes. METHODS: Corneas, irises, ciliary bodies, lenses, and retinas were obtained from cadaver globes 0-1/2 hours postmortem of 6 male donors (age: 44-61 years). The metabolic profile of tissues was investigated with HR MAS 1H NMR spectroscopy. RESULTS: A total of 29 metabolites were assigned in the NMR spectra of the eye tissues. Significant differences between tissues were revealed in contents of the most distant eye-tissues, while irises and ciliary bodies showed minimal biochemical differences. ATP, acetate, choline, glutamate, lactate, myoinositol, and taurine were identified as the primary biochemical compounds responsible for differentiation of the eye tissues. CONCLUSIONS: In this study we showed for the first time the results of the analysis of the main human eye tissues with NMR spectroscopy. The biochemical contents of the selected tissues seemed to correspond to their primary anatomical and functional attributes, the way of the delivery of the nutrients, and the location of the tissues in the eye.

| S-EPMC4265547 | biostudies-other

NMR hyperfine shifts in blue copper proteins: a quantum chemical investigation.

Project description:We present the results of the first quantum chemical investigations of 1H NMR hyperfine shifts in the blue copper proteins (BCPs): amicyanin, azurin, pseudoazurin, plastocyanin, stellacyanin, and rusticyanin. We find that very large structural models that incorporate extensive hydrogen bond networks, as well as geometry optimization, are required to reproduce the experimental NMR hyperfine shift results, the best theory vs experiment predictions having R2 = 0.94, a slope = 1.01, and a SD = 40.5 ppm (or approximately 4.7% of the overall approximately 860 ppm shift range). We also find interesting correlations between the hyperfine shifts and the bond and ring critical point properties computed using atoms-in-molecules theory, in addition to finding that hyperfine shifts can be well-predicted by using an empirical model, based on the geometry-optimized structures, which in the future should be of use in structure refinement.

| S-EPMC2761745 | biostudies-literature

Quantum Chemical Insight into 1,2-Shift Rearrangement in Bromination of Allylaryls

Project description: Not available

| S-EPMC10652718 | biostudies-literature

In situ NMR spectroscopy of supercapacitors: insight into the charge storage mechanism.

Project description:Electrochemical capacitors, commonly known as supercapacitors, are important energy storage devices with high power capabilities and long cycle lives. Here we report the development and application of in situ nuclear magnetic resonance (NMR) methodologies to study changes at the electrode-electrolyte interface in working devices as they charge and discharge. For a supercapacitor comprising activated carbon electrodes and an organic electrolyte, NMR experiments carried out at different charge states allow quantification of the number of charge storing species and show that there are at least two distinct charge storage regimes. At cell voltages below 0.75 V, electrolyte anions are increasingly desorbed from the carbon micropores at the negative electrode, while at the positive electrode there is little change in the number of anions that are adsorbed as the voltage is increased. However, above a cell voltage of 0.75 V, dramatic increases in the amount of adsorbed anions in the positive electrode are observed while anions continue to be desorbed at the negative electrode. NMR experiments with simultaneous cyclic voltammetry show that supercapacitor charging causes marked changes to the local environments of charge storing species, with periodic changes of their chemical shift observed. NMR calculations on a model carbon fragment show that the addition and removal of electrons from a delocalized system should lead to considerable increases in the nucleus-independent chemical shift of nearby species, in agreement with our experimental observations.

| S-EPMC3876747 | biostudies-literature

Quantum chemical 13C(alpha) chemical shift calculations for protein NMR structure determination, refinement, and validation.

Project description:A recently determined set of 20 NMR-derived conformations of a 48-residue all-alpha-helical protein, (PDB ID code 2JVD), is validated here by comparing the observed (13)C(alpha) chemical shifts with those computed at the density functional level of theory. In addition, a recently introduced physics-based method, aimed at determining protein structures by using NOE-derived distance constraints together with observed and computed (13)C(alpha) chemical shifts, was applied to determine a new set of 10 conformations, (Set-bt), as a blind test for the same protein. A cross-validation of these two sets of conformations in terms of the agreement between computed and observed (13)C(alpha) chemical shifts, several stereochemical quality factors, and some NMR quality assessment scores reveals the good quality of both sets of structures. We also carried out an analysis of the agreement between the observed and computed (13)C(alpha) chemical shifts for a slightly longer construct of the protein solved by x-ray crystallography at 2.0-A resolution (PDB ID code 3BHP) with an identical amino acid residue sequence to the 2JVD structure for the first 46 residues. Our results reveal that both of the NMR-derived sets, namely 2JVD and Set-bt, are somewhat better representations of the observed (13)C(alpha) chemical shifts in solution than the 3BHP crystal structure. In addition, the (13)C(alpha)-based validation analysis appears to be more sensitive to subtle structural differences across the three sets of structures than any other NMR quality-assessment scores used here, and, although it is computationally intensive, this analysis has potential value as a standard procedure to determine, refine, and validate protein structures.

| S-EPMC2567219 | biostudies-literature

Metabolomics specificity of tuberculosis plasma revealed by (1)H NMR spectroscopy.

Project description:Tuberculosis (TB) is a communicable disease of major global importance and causes metabolic disorder of the patients. In a previous study, we found that the plasma metabolite profile of TB patients differs from that of healthy control subjects based on nuclear magnetic resonance (NMR) spectroscopy. In order to evaluate the TB specificity of the metabolite profile, a total of 110 patients, including 40 with diabetes, 40 with malignancy, and 30 with community-acquired pneumonia (CAP), assessed by NMR spectroscopy, and compared to those of patients with TB. Based on the orthogonal partial least-squares discriminant analysis (OPLS-DA), the metabolic profiles of these diseases were significant different, as compared to the healthy controls and TB patients, respectively. The score plots of the OPLS-DA model demonstrated that TB was easily distinguishable from diabetes, CAP and malignancy. Plasma levels of ketone bodies, lactate, and pyruvate were increased in TB patient compared to healthy control, but lower than CAP and malignancy. We conclude that the metabolic profiles were TB-specific and reflected MTB infection. Our results strongly support the NMR spectroscopy-based metabolomics could contribute to an improved understanding of disease mechanisms and may offer clues to new TB clinic diagnosis and therapies.

| S-EPMC4428961 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data