Deconvoluting low yield from weak potency in direct-to-biology workflows with machine learning

McCorkindale, William; Filep, Mihajlo; London, Nir; Lee, Alpha A.; King-Smith, Emma

doi:10.1039/d3md00719g

RSC Med. Chem.

2024

DOI: 10.1039/d3md00719g

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Deconvoluting low yield from weak potency in direct-to-biology workflows with machine learning

William McCorkindale,

Mihajlo Filep,

Nir London

et al.

Abstract: High throughput and rapid biological evaluation of small molecules is an essential factor in drug discovery and development. Direct-to-Biology (D2B), whereby compound purification is foregone, has emerged as a viable...

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Expedited SARS‐CoV‐2 Main Protease Inhibitor Discovery through Modular ‘Direct‐to‐Biology’ Screening

Wilders,

Biggs,

Rowe

et al. 2024

Angewandte Chemie

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Reactive fragment (RF) screening has emerged as an efficient method for ligand discovery across the proteome, irrespective of a target’s perceived tractability. To date, however, the efficiency of subsequent optimisation campaigns has largely been low‐throughput, constrained by the need for synthesis and purification of target compounds. We report a high‐throughput platform for ‘direct‐to‐biology’ (D2B) screening of cysteine‐targeting chloroacetamide RFs, wherein synthesis is performed in 384‐well plates allowing direct assessment in downstream biological assays without purification. Here, the developed platform was used to optimise inhibitors of SARS‐CoV‐2 main protease (MPro), an established drug target for the treatment of COVID‐19. An initial RF hit was developed into a series of potent inhibitors, and further exploration using D2B screening enabled a ‘switch’ to a reversible inhibitor series. This example of ligand discovery for MPro illustrates the acceleration that D2B chemistry can offer for optimising RFs towards covalent inhibitor candidates, as well as providing future impetus to explore the evolution of RFs into non‐covalent ligands.

show abstract

Expedited SARS‐CoV‐2 Main Protease Inhibitor Discovery through Modular ‘Direct‐to‐Biology’ Screening

Wilders,

Biggs,

Rowe

et al. 2024

Angewandte Chemie

View full text Add to dashboard Cite

show abstract

Expedited SARS‐CoV‐2 Main Protease Inhibitor Discovery through Modular ‘Direct‐to‐Biology’ Screening

Wilders,

Biggs,

Rowe

et al. 2024

Angew Chem Int Ed

View full text Add to dashboard Cite

show abstract

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Deconvoluting low yield from weak potency in direct-to-biology workflows with machine learning

Abstract: High throughput and rapid biological evaluation of small molecules is an essential factor in drug discovery and development. Direct-to-Biology (D2B), whereby compound purification is foregone, has emerged as a viable...

Cited by 2 publications

References 27 publications

Expedited SARS‐CoV‐2 Main Protease Inhibitor Discovery through Modular ‘Direct‐to‐Biology’ Screening

Expedited SARS‐CoV‐2 Main Protease Inhibitor Discovery through Modular ‘Direct‐to‐Biology’ Screening

Expedited SARS‐CoV‐2 Main Protease Inhibitor Discovery through Modular ‘Direct‐to‐Biology’ Screening

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