LC‐MS Bioanalysis of Nucleotides

Cohen, Sabine; Gagnieu, Marie‐Claude; Lefèbvre, Isabelle; Guitton, Jérôme

doi:10.1002/9781118671276.ch44

Cited by 3 publications

(1 citation statement)

References 30 publications

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“…ADP-ribosylation is a ubiquitous post-translational protein modification that regulates important cellular processes. 1 Poly ADP-ribose polymerases (PARPs) constitute a family of enzymes that form ADP-ribose protein modifications from nicotinamide adenine dinucleotide (NAD + ) substrates. 2 PARP-modulating pharmaceuticals are of high medical importance, and four inhibitors of PARP1 are in clinical use.…”

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confidence: 99%

Integrating DNA-encoded chemical libraries with virtual combinatorial library screening: Optimizing a PARP10 inhibitor

Lemke

Ravenscroft

Rueb

et al. 2020

Bioorganic & Medicinal Chemistry Letters

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Two critical steps in drug development are 1) the discovery of molecules that have the desired effects on a target, and 2) the optimization of such molecules into lead compounds with the required potency and pharmacokinetic properties for translation. DNA-encoded chemical libraries (DECLs) can nowadays yield hits with unprecedented ease, and lead-optimization is becoming the limiting step. Here we integrate DECL screening with structure-based computational methods to streamline the development of lead compounds. The presented workflow consists of enumerating a virtual combinatorial library (VCL) derived from a DECL screening hit and using computational binding prediction to identify molecules with enhanced properties relative to the original DECL hit. As proof-of-concept demonstration, we applied this approach to identify an inhibitor of PARP10 that is more potent and druglike than the original DECL screening hit.

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confidence: 99%