The Impact of Drug Metabolism in Contemporary Drug Discovery: New Opportunities and Challenges for Mass Spectrometry

Biophysical methods such as mass spectrometry, surface plasmon resonance, nuclear magnetic resonance, and both differential scanning isothermal titration calorimetry are now well established as key components of the early drug discovery process. These approaches are used successfully for a range of activities, including assay development, primary screening, hit confirmation and detailed mechanistic characterisation of compound binding. Matching the speed, sensitivity and information content of the various techniques to the generation of critical data and information required at each phase of the drug discovery process has been key. This review describes the framework by which these methods have been applied in the drug discovery process and provides case studies to exemplify the impact.

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Characterization of the Impact of Drug Metabolism on the Gas-Phase Structures of Drugs Using Ion Mobility-Mass Spectrometry

Analytical Chemistry ◽

10.1021/acs.analchem.9b03292 ◽

2019 ◽

Vol 91 (22) ◽

pp. 14498-14507 ◽

Cited By ~ 1

Author(s):

Dylan H. Ross ◽

Ryan P. Seguin ◽

Libin Xu

Keyword(s):

Mass Spectrometry ◽

Drug Metabolism ◽

Gas Phase ◽

Ion Mobility ◽

Ion Mobility Mass Spectrometry ◽

Phase Structures ◽

The Impact

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Polyphenol Profiling of Chestnut Pericarp, Integument and Curing Water Extracts to Qualify These Food By-Products as a Source of Antioxidants

Molecules ◽

10.3390/molecules26082335 ◽

2021 ◽

Vol 26 (8) ◽

pp. 2335

Author(s):

Gabriella Pinto ◽

Sabrina De Pascale ◽

Maria Aponte ◽

Andrea Scaloni ◽

Francesco Addeo ◽

...

Keyword(s):

Mass Spectrometry ◽

Negative Impact ◽

Tap Water ◽

Time Of Flight ◽

The Other ◽

Curing Process ◽

Flight Mass Spectrometry ◽

Water Curing ◽

The Impact ◽

By Products

Plant polyphenols have beneficial antioxidant effects on human health; practices aimed at preserving their content in foods and/or reusing food by-products are encouraged. The impact of the traditional practice of the water curing procedure of chestnuts, which prevents insect/mould damage during storage, was studied to assess the release of polyphenols from the fruit. Metabolites extracted from pericarp and integument tissues or released in the medium from the water curing process were analyzed by matrix-assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS) and electrospray-quadrupole-time of flight-mass spectrometry (ESI-qTOF-MS). This identified: (i) condensed and hydrolyzable tannins made of (epi)catechin (procyanidins) and acid ellagic units in pericarp tissues; (ii) polyphenols made of gallocatechin and catechin units condensed with gallate (prodelphinidins) in integument counterparts; (iii) metabolites resembling those reported above in the wastewater from the chestnut curing process. Comparative experiments were also performed on aqueous media recovered from fruits treated with processes involving: (i) tap water; (ii) tap water containing an antifungal Lb. pentosus strain; (iii) wastewater from a previous curing treatment. These analyses indicated that the former treatment determines a 6–7-fold higher release of polyphenols in the curing water with respect to the other ones. This event has a negative impact on the luster of treated fruits but qualifies the corresponding wastes as a source of antioxidants. Such a phenomenon does not occur in wastewater from the other curing processes, where the release of polyphenols was reduced, thus preserving the chestnut’s appearance. Polyphenol profiling measurements demonstrated that bacterial presence in water hampered the release of pericarp metabolites. This study provides a rationale to traditional processing practices on fruit appearance and qualifies the corresponding wastes as a source of bioactive compounds for other nutraceutical applications.

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High-Throughput Affinity Selection Mass Spectrometry Using SAMDI-MS to Identify Small-Molecule Binders of the Human Rhinovirus 3C Protease

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/24725552211023211 ◽

2021 ◽

pp. 247255522110232

Author(s):

Michael D. Scholle ◽

Doug McLaughlin ◽

Zachary A. Gurard-Levin

Keyword(s):

Mass Spectrometry ◽

Drug Discovery ◽

High Throughput ◽

High Throughput Screening ◽

Human Rhinovirus ◽

Binding Potential ◽

Affinity Selection ◽

Response Curves ◽

Desorption Ionization ◽

Self Assembled

Affinity selection mass spectrometry (ASMS) has emerged as a powerful high-throughput screening tool used in drug discovery to identify novel ligands against therapeutic targets. This report describes the first high-throughput screen using a novel self-assembled monolayer desorption ionization (SAMDI)–ASMS methodology to reveal ligands for the human rhinovirus 3C (HRV3C) protease. The approach combines self-assembled monolayers of alkanethiolates on gold with matrix-assisted laser desorption ionization time-of-flight (MALDI TOF) mass spectrometry (MS), a technique termed SAMDI-ASMS. The primary screen of more than 100,000 compounds in pools of 8 compounds per well was completed in less than 8 h, and informs on the binding potential and selectivity of each compound. Initial hits were confirmed in follow-up SAMDI-ASMS experiments in single-concentration and dose–response curves. The ligands identified by SAMDI-ASMS were further validated using differential scanning fluorimetry (DSF) and in functional protease assays against HRV3C and the related SARS-CoV-2 3CLpro enzyme. SAMDI-ASMS offers key benefits for drug discovery over traditional ASMS approaches, including the high-throughput workflow and readout, minimizing compound misbehavior by using smaller compound pools, and up to a 50-fold reduction in reagent consumption. The flexibility of this novel technology opens avenues for high-throughput ASMS assays of any target, thereby accelerating drug discovery for diverse diseases.

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Quantitative Analysis of Pyrazines and Their Perceptual Interactions in Soy Sauce Aroma Type Baijiu

Foods ◽

10.3390/foods10020441 ◽

2021 ◽

Vol 10 (2) ◽

pp. 441

Author(s):

Yan Yan ◽

Shuang Chen ◽

Yao Nie ◽

Yan Xu

Keyword(s):

Mass Spectrometry ◽

Quantitative Analysis ◽

Ultra Performance Liquid Chromatography ◽

Alcohol Solution ◽

Soy Sauce ◽

Tandem Mass ◽

Odor Thresholds ◽

Quantitative Results ◽

Odor Activity Value ◽

The Impact

Pyrazines are important compounds in soy sauce aroma type Baijiu (SSAB). In this work, a total of 16 pyrazines were analyzed using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC–MS/MS) in SSAB. The quantitative results showed that 2,3,5,6-tetramethylpyrazine, 2,6-dimethylpyrazine and 2,3,5-trimethylpyrazine were the three most concentrated pyrazines. The highest odor activity value (OAV) was determined for 2-ethyl-3,5-dimethylpyrazine. Quantitative analysis combined with descriptive sensory analysis revealed that sub-threshold pyrazines (2,3-dimethylpyrazine, 2,3-diethylpyrazine, 2,3-diethyl-5-methylpyrazine and 2-acetyl-3-methylpyrazine) are significantly correlated with the roasted aroma in SSAB. Our study focused on the impact of sub-threshold pyrazines on the perception of roasted aroma in SSAB. The effect of the sub-threshold pyrazines was detected by the addition of various pyrazines in SSAB samples, despite their sub-threshold concentrations. Furthermore, the presence of sub-threshold pyrazines in dilute alcohol solution resulted in a significant reduction in the odor thresholds of supra-threshold pyrazines. Sensory investigation indicated that pyrazines have a synergistic effect on the perception of roasted aroma. The results highlighted the contribution of some pyrazines to the roasted aroma in SSAB despite their sub-threshold concentrations.

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A systematic approach to development of analytical scale and microflow-based liquid chromatography coupled to mass spectrometry metabolomics methods to support drug discovery and development

Journal of Chromatography A ◽

10.1016/j.chroma.2021.462047 ◽

2021 ◽

Vol 1642 ◽

pp. 462047

Author(s):

Sarah Geller ◽

Harvey Lieberman ◽

Alla Kloss ◽

Alexander R. Ivanov

Keyword(s):

Mass Spectrometry ◽

Liquid Chromatography ◽

Drug Discovery ◽

Systematic Approach ◽

Drug Discovery And Development ◽

Analytical Scale

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Matrix-assisted laser desorption ionisation (MALDI) mass spectrometry (MS): basics and clinical applications

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2019-0868 ◽

2020 ◽

Vol 58 (6) ◽

pp. 883-896 ◽

Cited By ~ 3

Author(s):

Muhammad Zubair Israr ◽

Dennis Bernieh ◽

Andrea Salzano ◽

Shabana Cassambai ◽

Yoshiyuki Yazaki ◽

...

Keyword(s):

Mass Spectrometry ◽

Laser Desorption ◽

Maldi Mass Spectrometry ◽

Clinical Applications ◽

Clinical Diagnostics ◽

Maldi Ms ◽

Therapeutic Drug ◽

The Impact ◽

Matrix Assisted Laser ◽

Matrix Assisted Laser Desorption

AbstractBackgroundMatrix-assisted laser desorption ionisation (MALDI) mass spectrometry (MS) has been used for more than 30 years. Compared with other analytical techniques, it offers ease of use, high throughput, robustness, cost-effectiveness, rapid analysis and sensitivity. As advantages, current clinical techniques (e.g. immunoassays) are unable to directly measure the biomarker; rather, they measure secondary signals. MALDI-MS has been extensively researched for clinical applications, and it is set for a breakthrough as a routine tool for clinical diagnostics.ContentThis review reports on the principles of MALDI-MS and discusses current clinical applications and the future clinical prospects for MALDI-MS. Furthermore, the review assesses the limitations currently experienced in clinical assays, the advantages and the impact of MALDI-MS to transform clinical laboratories.SummaryMALDI-MS is widely used in clinical microbiology for the screening of microbial isolates; however, there is scope to apply MALDI-MS in the diagnosis, prognosis, therapeutic drug monitoring and biopsy imaging in many diseases.OutlookThere is considerable potential for MALDI-MS in clinic as a tool for screening, profiling and imaging because of its high sensitivity and specificity over alternative techniques.

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Miniaturization and Automation of a Human In Vitro Blood–Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery

Pharmaceutics ◽

10.3390/pharmaceutics13060892 ◽

2021 ◽

Vol 13 (6) ◽

pp. 892

Author(s):

Elisa L. J. Moya ◽

Elodie Vandenhaute ◽

Eleonora Rizzi ◽

Marie-Christine Boucau ◽

Johan Hachani ◽

...

Keyword(s):

Drug Discovery ◽

Blood Brain Barrier ◽

Early Stage ◽

Molecular Transport ◽

Brain Barrier ◽

Blood Brain ◽

Cns Drugs ◽

The Impact ◽

The Brain

Central nervous system (CNS) diseases are one of the top causes of death worldwide. As there is a difficulty of drug penetration into the brain due to the blood–brain barrier (BBB), many CNS drugs treatments fail in clinical trials. Hence, there is a need to develop effective CNS drugs following strategies for delivery to the brain by better selecting them as early as possible during the drug discovery process. The use of in vitro BBB models has proved useful to evaluate the impact of drugs/compounds toxicity, BBB permeation rates and molecular transport mechanisms within the brain cells in academic research and early-stage drug discovery. However, these studies that require biological material (animal brain or human cells) are time-consuming and involve costly amounts of materials and plastic wastes due to the format of the models. Hence, to adapt to the high yields needed in early-stage drug discoveries for compound screenings, a patented well-established human in vitro BBB model was miniaturized and automated into a 96-well format. This replicate met all the BBB model reliability criteria to get predictive results, allowing a significant reduction in biological materials, waste and a higher screening capacity for being extensively used during early-stage drug discovery studies.

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