限制
IC50型
化学
DNA
组合化学
药理学
生物化学
医学
体外
机械工程
工程类
作者
Patrick R. Fitzgerald,Wesley G. Cochrane,Brian M. Paegel
标识
DOI:10.1021/acsmedchemlett.3c00159
摘要
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 tetrahydroisoquinoline) were validated as inhibitors (IC50 = 7 ± 2, 13 ± 2, and 1 ± 0.3 μM). Photochemical dose–response DEL screening data prioritized hits for synthesis, the rate-limiting step in DEL lead identification.
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