Integrating DNA-encoded chemical libraries with virtual combinatorial library screening: Optimizing a PARP10 inhibitor.
Department of Chemistry, McDaniel College, 2 College Hill, Westminster, MD 21157, USA.
Department of Medicinal Chemistry, Skaggs College of Pharmacy, University of Utah, 30 S 2000 E, Salt Lake City, UT 84112, USA.
Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, 301 Pharmacy Lane, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: [email protected]
Department of Chemistry, McDaniel College, 2 College Hill, Westminster, MD 21157, USA. Electronic address: [email protected]
Department of Medicinal Chemistry, Skaggs College of Pharmacy, University of Utah, 30 S 2000 E, Salt Lake City, UT 84112, USA. Electronic address: [email protected]
- Published Article
Bioorganic & medicinal chemistry letters
- Publication Date
Aug 05, 2020
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. Copyright © 2020 Elsevier Ltd. All rights reserved.
Report this publication
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
This record was last updated on 09/02/2020 and may not reflect the most current and accurate biomedical/scientific data available from NLM.
The corresponding record at NLM can be accessed at https://www.ncbi.nlm.nih.gov/pubmed/32768646