scholarly journals Rapid LC/MS/MS Method Development for Drug Discovery

2005 ◽  
Vol 77 (19) ◽  
pp. 389 A-394 A ◽  
Author(s):  
Xiaoying Xu ◽  
Jing Lan ◽  
Walter A. Korfmacher
Keyword(s):  
Drug Discovery ◽  
Method Development

scholarly journals Quantum–mechanical property prediction of solvated drug molecules: what have we learned from a decade of SAMPL blind prediction challenges?

2020 ◽  
Author(s):  
Nicolas Tielker ◽  
Lukas Eberlein ◽  
Gerhard Hessler ◽  
K. Friedemann Schmidt ◽  
Stefan Güssregen ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecule ◽  
Method Development ◽  
Biological Data ◽  
Quantum Mechanical ◽  
Model Assessment ◽  
Ligand Interaction ◽  
Blind Prediction ◽  
Mechanical Methods

Abstract Joint academic–industrial projects supporting drug discovery are frequently pursued to deploy and benchmark cutting-edge methodical developments from academia in a real-world industrial environment at different scales. The dimensionality of tasks ranges from small molecule physicochemical property assessment over protein–ligand interaction up to statistical analyses of biological data. This way, method development and usability both benefit from insights gained at both ends, when predictiveness and readiness of novel approaches are confirmed, but the pharmaceutical drug makers get early access to novel tools for the quality of drug products and benefit of patients. Quantum–mechanical and simulation methods particularly fall into this group of methods, as they require skills and expense in their development but also significant resources in their application, thus are comparatively slowly dripping into the realm of industrial use. Nevertheless, these physics-based methods are becoming more and more useful. Starting with a general overview of these and in particular quantum–mechanical methods for drug discovery we review a decade-long and ongoing collaboration between Sanofi and the Kast group focused on the application of the embedded cluster reference interaction site model (EC-RISM), a solvation model for quantum chemistry, to study small molecule chemistry in the context of joint participation in several SAMPL (Statistical Assessment of Modeling of Proteins and Ligands) blind prediction challenges. Starting with early application to tautomer equilibria in water (SAMPL2) the methodology was further developed to allow for challenge contributions related to predictions of distribution coefficients (SAMPL5) and acidity constants (SAMPL6) over the years. Particular emphasis is put on a frequently overlooked aspect of measuring the quality of models, namely the retrospective analysis of earlier datasets and predictions in light of more recent and advanced developments. We therefore demonstrate the performance of the current methodical state of the art as developed and optimized for the SAMPL6 pKa and octanol–water log P challenges when re-applied to the earlier SAMPL5 cyclohexane-water log D and SAMPL2 tautomer equilibria datasets. Systematic improvement is not consistently found throughout despite the similarity of the problem class, i.e. protonation reactions and phase distribution. Hence, it is possible to learn about hidden bias in model assessment, as results derived from more elaborate methods do not necessarily improve quantitative agreement. This indicates the role of chance or coincidence for model development on the one hand which allows for the identification of systematic error and opportunities toward improvement and reveals possible sources of experimental uncertainty on the other. These insights are particularly useful for further academia–industry collaborations, as both partners are then enabled to optimize both the computational and experimental settings for data generation.

Importance of mobile phase and injection solvent selection during rapid method development and sample analysis in drug discovery bioanalysis illustrated using convenient multiplexed LC-MS/MS

2010 ◽  
Vol 2 (4) ◽  
pp. 375 ◽  
Author(s):  
Jian Wang ◽  
Anne-Francoise Aubry ◽  
Georgia Cornelius ◽  
Christian Caporuscio ◽  
Bogdan Sleczka ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Rapid Method ◽  
Mobile Phase ◽  
Method Development ◽  
Sample Analysis ◽  
Solvent Selection

Tiered analytics for purity assessment of macrocyclic peptides in drug discovery: Analytical consideration and method development

2017 ◽  
Vol 138 ◽  
pp. 166-174 ◽  
Author(s):  
Jingfang (Jenny) Qian Cutrone ◽  
Xiaohua (Stella) Huang ◽  
Edward S. Kozlowski ◽  
Ye Bao ◽  
Yingzi Wang ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Method Development ◽  
Purity Assessment ◽  
Analytical Consideration ◽  
Macrocyclic Peptides

scholarly journals Neglected sulfur(vi) pharmacophores in drug discovery: exploration of novel chemical space by the interplay of drug design and method development

2019 ◽  
Vol 6 (8) ◽  
pp. 1319-1324 ◽  
Author(s):  
U. Lücking
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Method Development ◽  
Chemical Space

The key learnings of the utilization of sulfoximines, sulfondiimines and sulfonimidamides in drug discovery at Bayer AG are shared.

Acoustic Ejection Mass Spectrometry: A Fully Automatable Technology for High-Throughput Screening in Drug Discovery

2021 ◽  
pp. 247255522110281
Author(s):  
Roman P. Simon ◽  
Tim T. Häbe ◽  
Robert Ries ◽  
Martin Winter ◽  
Yuting Wang ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Drug Discovery ◽  
High Throughput ◽  
High Throughput Screening ◽  
Large Scale ◽  
Method Development ◽  
Accurate Determination ◽  
Adenosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Label Free

Acoustic droplet ejection (ADE)–open port interface (OPI)–mass spectrometry (MS) has recently been introduced as a versatile analytical method that combines fast and contactless acoustic sampling with sensitive and accurate electrospray ionization (ESI)–MS-based analyte detection. The potential of the technology to provide label-free measurements in subsecond analytical cycle times makes it an attractive option for high-throughput screening (HTS). Here, we report the first implementation of ADE-OPI-MS in a fully automated HTS environment, based on the example of a biochemical assay aiming at the identification of small-molecule inhibitors of the cyclic guanosine monophosphate–adenosine monophosphate (GMP-AMP) synthase (cGAS). First, we describe the optimization of the method to enable sensitive and accurate determination of enzyme activity and inhibition in miniaturized 1536-well microtiter plate format. Then we show both results from a validation single-concentration screen using a test set of 5500 compounds, and the subsequent concentration–response testing of selected hits in direct comparison with a previously established matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) readout. Finally, we present the development of an in-line OPI cleaning procedure aiming to match the instrument robustness required for large-scale HTS campaigns. Overall, this work points to critical method development parameters and provides guidance for the establishment of integrated ADE-OPI-MS as HTS-compatible technology for early drug discovery.

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