Integrating DNA-encoded chemical libraries with virtual combinatorial library screening: Optimizing a PARP10 inhibitor.
Combinatorial Chemistry Techniques
DNA
/ chemistry
Drug Discovery
Drug Evaluation, Preclinical
Enzyme Assays
Humans
Molecular Docking Simulation
Poly(ADP-ribose) Polymerases
/ metabolism
Proof of Concept Study
Protein Binding
Proto-Oncogene Proteins
/ antagonists & inhibitors
Small Molecule Libraries
/ chemistry
Computer-guided drug discovery
DNA-encoded chemical libraries
Hit-to-lead development
Poly-(ADP-ribose) polymerase
Virtual combinatorial libraries
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
01 10 2020
01 10 2020
Historique:
received:
16
07
2020
revised:
25
07
2020
accepted:
02
08
2020
pubmed:
10
8
2020
medline:
22
6
2021
entrez:
10
8
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32768646
pii: S0960-894X(20)30575-8
doi: 10.1016/j.bmcl.2020.127464
pmc: PMC7530011
mid: NIHMS1620493
pii:
doi:
Substances chimiques
Proto-Oncogene Proteins
0
Small Molecule Libraries
0
DNA
9007-49-2
PARP10 protein, human
EC 2.4.2.30
Poly(ADP-ribose) Polymerases
EC 2.4.2.30
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
127464Subventions
Organisme : NCI NIH HHS
ID : R01 CA249190
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM132299
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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