ACS Combinatorial Science · 2014 · 42 citations · 27 references
PharmacyChemistryMedicinal ChemistryDrug DesignDrug DiscoveryStructure-activity RelationshipsChemical Library DesignHit DiscoveryHit-to-lead OptimizationLead DiscoveryLibrary ScreeningLigand-based DesignAbsolute PotencyBinding ConstantsEarly Drug DiscoveryIterative ScreeningLead Compound DiscoveryStructure - Activity Relationship OptimizationStructure-based Lead DiscoveryStructure-based Screening
Primary hits that arise from screening one bead one compound (OBOC) libraries against a target of interest rarely have high potency. However, there has been little work focused on the development of an efficient workflow for primary hit improvement. In this study, we show that by characterizing the binding constants for all of the hits that arise from a screen, structure-activity relationship (SAR) data can be obtained to inform the design of "derivative libraries" of a primary hit that can then be screened under more demanding conditions to obtain improved compounds. Here, we demonstrate the rapid improvement of a primary hit against matrix metalloproteinase-14 using this approach.
27
A new type of synthetic peptide library for identifying ligand-binding activity
Kit S. Lam, Sydney E. Salmon, Evan M. Hersh et al. · Nature · 1991 · 1.8K citations