Dose–Response Activity-Based DNA-Encoded Library Screening

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2023-08-21 DOI:10.1021/acsmedchemlett.3c00159

Patrick R. Fitzgerald, Wesley G. Cochrane and Brian M. Paegel*,

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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 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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基于剂量反应活性的dna编码文库筛选

剂量反应，或“顺从”行为，增加了对放映成功影片真实性的信心。在这里，我们展示了剂量响应固相dna编码文库(DEL)筛选。微流控液滴中的化合物剂量是通过光裂解DEL珠的紫外强度来调节的。在不同的紫外线强度下，筛选了55,296个成员的DEL对模型酶药物靶因子Xa (FXa)和autotaxin (ATX)的抑制作用。两种屏幕都产生了光化学剂量依赖的命中率(在100/30%的紫外线照射下，FXa命中率为0.08/0.05%;在100/20%的紫外线照射下，ATX命中率为0.24/0.08%)。FXa hit含有反映FXa抑制剂的结构，其中4个hit抑制FXa (IC50分别为4.2±0.1、7.4±0.3、9.0±0.3和19±2 μM)。结果表明，ATX命中的2个二氢苯并咪唑酮和1个四氢异喹啉为抑制剂(IC50分别为7±2、13±2和1±0.3 μM)。光化学剂量响应DEL筛选数据优先考虑合成命中，这是DEL导联鉴定的限速步骤。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.

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