Dose-Response Activity-Based DNA-Encoded Library Screening.

ABSTRACT: Dose-response, or "conforming" behavior, increases confidence in a screening hit's authenticity. Here, we demonstrate dose-response solid-phase DNA-encoded library (DEL) screening. Compound dose in microfluidic droplets is modulated via the UV intensity of photocleavage from DEL beads. A 55,296-member DEL was screened at different UV intensities against model enzyme drug targets factor Xa (FXa) and autotaxin (ATX). Both screens yielded photochemical dose-dependent hit rates (FXa hit rates of 0.08/0.05% at 100/30% UV exposure; ATX hit rates of 0.24/0.08% at 100/20% UV exposure). FXa hits contained structures reflective of FXa inhibitors and four hits inhibited FXa (IC₅₀ = 4.2 ± 0.1, 7.4 ± 0.3, 9.0 ± 0.3, and 19 ± 2 μM.) The top ATX hits (two dihydrobenzamidazolones and a tetrahyd

SUBMITTER: Fitzgerald PR 

PROVIDER: S-EPMC10510511 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature