Integrated and automated high-throughput purification of libraries on microscale

Ginsburg‐Moraff, Carol; Grob, Jonathan E.; Chin, Karl; Eastman, Grant; Wildhaber, Sandra; Bayliss, Mark; Mues, Heinrich M.; Palmieri, Marco; Poirier, Jennifer; Reck, Marcel; Luneau, Alexandre; Rodde, Stephane; Reilly, John M.; Wagner, Trixie; Brocklehurst, Cara E.; Wyler, R.; Dunstan, David W.; Marziale, Alexander N.

doi:10.1016/j.slast.2022.08.002

Cited by 8 publications

(7 citation statements)

References 52 publications

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“…Upon completion of synthetic chemistry steps and workup, the crude chemical matter is subjected to an integrated, liquid chromatography–mass spectrometry (LC-MS)-based workflow combining analysis, isolation, quality control, and reformatting for subsequent profiling. A recent publication from our group describes the process and hardware in more detail . Aliquots are taken from the crude reaction mixtures using an EP Motion liquid-handling platform, and each sample is analyzed under both acidic and basic conditions via ultra-high-pressure liquid chromatography–mass spectrometry (UPLC-MS).…”

Section: Resultsmentioning

confidence: 99%

“…A recent publication from our group describes the process and hardware in more detail. 28 Aliquots are taken from the crude reaction mixtures using an EP Motion liquid-handling platform, and each sample is analyzed under both acidic and basic conditions via ultra-high-pressure liquid chromatography−mass spectrometry (UPLC-MS). The application of orthogonal liquid chromatography conditions in combination with various detector technologies such as mass spectroscopy, UV/vis spectroscopy, and charged aerosol detection (CAD) allows for a detailed understanding of the crude reaction profile.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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MicroCycle: An Integrated and Automated Platform to Accelerate Drug Discovery

Brocklehurst,

Altmann,

Bon

et al. 2024

J. Med. Chem.

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We herein describe the development and application of a modular technology platform which incorporates recent advances in plate-based microscale chemistry, automated purification, in situ quantification, and robotic liquid handling to enable rapid access to high-quality chemical matter already formatted for assays. In using microscale chemistry and thus consuming minimal chemical matter, the platform is not only efficient but also follows green chemistry principles. By reorienting existing high-throughput assay technology, the platform can generate a full package of relevant data on each set of compounds in every learning cycle. The multiparameter exploration of chemical and property space is hereby driven by active learning models. The enhanced compound optimization process is generating knowledge for drug discovery projects in a time frame never before possible.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

MicroCycle: An Integrated and Automated Platform to Accelerate Drug Discovery

Brocklehurst,

Altmann,

Bon

et al. 2024

J. Med. Chem.

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“…Novartis has built automated platforms for rapid purification and quantification of chemical libraries including reformatting of chemical matter to 10 mM dimethyl sulfoxide stock solutions. This fully integrated workflow features tailored conditions for preparative reversed-phase (RP) high-performance liquid chromatography (HPLC)–MS on microscale based on analytical data, online fraction quality control, and Charged Aerosol Detection (CAD)–based quantification as well as automated reformatting to enable rapid purification of chemical libraries ( 29 ). The SLAP products synthesized and purified were subsequently subjected to miniaturized automated profiling assays to give a wealth of multiparameter data describing their properties.…”

Section: Resultsmentioning

confidence: 99%

High-throughput synthesis provides data for predicting molecular properties and reaction success

Götz,

Jackl,

Jindakun

et al. 2023

Sci. Adv.

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The generation of attractive scaffolds for drug discovery efforts requires the expeditious synthesis of diverse analogues from readily available building blocks. This endeavor necessitates a trade-off between diversity and ease of access and is further complicated by uncertainty about the synthesizability and pharmacokinetic properties of the resulting compounds. Here, we document a platform that leverages photocatalytic N-heterocycle synthesis, high-throughput experimentation, automated purification, and physicochemical assays on 1152 discrete reactions. Together, the data generated allow rational predictions of the synthesizability of stereochemically diverse C-substituted N-saturated heterocycles with deep learning and reveal unexpected trends on the relationship between structure and properties. This study exemplifies how organic chemists can exploit state-of-the-art technologies to markedly increase throughput and confidence in the preparation of drug-like molecules.

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“…Significant progress has also been made in multidimensional liquid chromatography (LC) systems , that expand the available separation space for HTE analysis and purification. The development of integrated platforms , for automating DMT steps can also increase process efficiencies.…”

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confidence: 99%

Predictions of Chromatography Methods by Chemical Structure Similarity to Accelerate High-Throughput Medicinal Chemistry

Wang,

Yen,

Beck

et al. 2024

ACS Med. Chem. Lett.

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We introduce a new workflow that relies heavily on chemical quantitative structure-retention relationship (QSRR) models to accelerate method development for micro/mini-scale highthroughput purification (HTP). This provides faster access to new active pharmaceutical ingredients (APIs) through high-throughput experimentation (HTE). By comparing fingerprint structural similarity (e.g., Tanimoto index) with small training data sets containing a few hundred diverse small molecule antagonists of a lipid metabolizing enzyme, we can predict retention time (RT) of new compounds. Machine learning (ML) helps to identify optimal separation conditions for purification without performing the traditional crude QC step involving ultrahigh performance liquid chromatography (UHPLC) analyses of each compound. This greenchemistry approach with the use of predictive tools reduces cost and significantly shortens the design-make-test (DMT) cycle of new drugs by way of HTE.

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Integrated and automated high-throughput purification of libraries on microscale

Cited by 8 publications

References 52 publications

MicroCycle: An Integrated and Automated Platform to Accelerate Drug Discovery

MicroCycle: An Integrated and Automated Platform to Accelerate Drug Discovery

High-throughput synthesis provides data for predicting molecular properties and reaction success

Predictions of Chromatography Methods by Chemical Structure Similarity to Accelerate High-Throughput Medicinal Chemistry

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